67 results on '"Luoting Yu"'
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2. The anthelmintic drug niclosamide induces apoptosis, impairs metastasis and reduces immunosuppressive cells in breast cancer model.
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Tinghong Ye, Ying Xiong, Yupeng Yan, Yong Xia, Xuejiao Song, Li Liu, Deliang Li, Ningyu Wang, Lidan Zhang, Yongxia Zhu, Jun Zeng, Yuquan Wei, and Luoting Yu
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Medicine ,Science - Abstract
Breast carcinoma is the most common female cancer with considerable metastatic potential. Discovery of new therapeutic approaches for treatment of metastatic breast cancer is still needed. Here, we reported our finding with niclosamide, an FDA approved anthelmintic drug. The potency of niclosamide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that niclosamide showed a dramatic growth inhibition against breast cancer cell lines and induced apoptosis of 4T1 cells in a dose-dependent manner. Further, Western blot analysis demonstrated the occurrence of its apoptosis was associated with activation of Cleaved caspases-3, down-regulation of Bcl-2, Mcl-1 and Survivin. Moreover, niclosamide blocked breast cancer cells migration and invasion, and the reduction of phosphorylated STAT3(Tyr705), phosphorylated FAK(Tyr925) and phosphorylated Src(Tyr416) were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 20 mg/kg/d niclosamide suppressed 4T1 tumor growth without detectable toxicity. Histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, VEGF-positive cells and microvessel density (MVD) and an increase in Cleaved caspase-3-positive cells upon niclosamide. Notably, niclosamide reduced the number of myeloid-derived suppressor cells (MDSCs) in tumor tissues and blocked formation of pulmonary metastases. Taken together, these results demonstrated that niclosamide may be a promising candidate for breast cancer.
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- 2014
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3. Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2
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Yongxia Zhu, Rong Hu, Tinghong Ye, Xiuli Wu, Wei Wei, Hualong He, Luoting Yu, Xi Hu, Qi-Wei Wang, Zhihao Liu, Ning-Yu Wang, Xingping Su, Shu-Yan Zhou, and Qiangsheng Zhang
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Methyltransferase ,Ubiquitin-Protein Ligases ,Proteolysis ,Antineoplastic Agents ,Phthalimides ,macromolecular substances ,01 natural sciences ,03 medical and health sciences ,Downregulation and upregulation ,Cell Line, Tumor ,Drug Discovery ,medicine ,SUZ12 ,Humans ,Gene silencing ,Enhancer of Zeste Homolog 2 Protein ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,biology ,Chemistry ,EZH2 ,Ubiquitination ,0104 chemical sciences ,Cell biology ,010404 medicinal & biomolecular chemistry ,Drug Design ,Benzamides ,Cancer cell ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,PRC2 - Abstract
EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.
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- 2021
4. Discovery of quinolone derivatives as antimycobacterial agents
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Lu Xiong, Chao Gao, Fei Teng, Kun-Lin Liu, Xiao Li, and Luoting Yu
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Tuberculosis ,Antimycobacterial Agents ,medicine.drug_class ,General Chemical Engineering ,Pharmacology ,01 natural sciences ,Mycobacterium tuberculosis ,03 medical and health sciences ,Minimum inhibitory concentration ,chemistry.chemical_compound ,medicine ,030304 developmental biology ,0303 health sciences ,biology ,010405 organic chemistry ,business.industry ,General Chemistry ,Quinolone ,medicine.disease ,biology.organism_classification ,In vitro ,0104 chemical sciences ,chemistry ,Vero cell ,business ,Lead compound - Abstract
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), is an important public health issue. Current first-line drugs administered to TB patients have been in use for over 40 years, whereas second-line drugs display strong side effects and poor compliance. Additionally, designing effective regimens to treat patients infected with multi- and extremely-drug-resistant (MDR and XDR) strains of TB is challenging. In this report, we screened our compound library and identified compound 1 with antituberculosis activity and a minimal inhibitory concentration (MIC) against M. tuberculosis of 20 μg mL−1. Structure optimization and the structure–activity relationship of 1 as the lead compound enabled the design and synthesis of a series of quinolone derivatives, 6a1–6a2, 6b1–6b36, 6c1, 6d1–6d14, 7a1–7a2, 7b1–7b2, 7c1, 8a1–8a5, 9a1–9a4 and 10a1–10a6. These compounds were evaluated in vitro for anti-tubercular activity against the M. tuberculosis H37Rv strain. Among them, compounds 6b6, 6b12 and 6b21 exhibited MIC values in the range of 1.2–3 μg mL−1 and showed excellent activity against the tested MDR-TB strain (MIC: 3, 2.9 and 0.9 μg mL−1, respectively). All three compounds were non-toxic toward A549 and Vero cells (>100 and >50 μg mL−1, respectively). In addition, an antibacterial spectrum test carried out using compound 6b21 showed that this compound specifically inhibits M. tuberculosis. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.
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- 2021
5. Design, synthesis and biological evaluation of 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one derivatives as potent FAK inhibitors for the treatment of ovarian cancer
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Xinyue Li, Wei Wei, Liu Zhihao, Yongxia Zhu, Hualong He, Chao Gao, Tinghong Ye, Zhanzhan Feng, Kai Ran, Yaojie Shi, Luoting Yu, and Ning-Yu Wang
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Mice, Nude ,Antineoplastic Agents ,Metastasis ,Focal adhesion ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Structure–activity relationship ,Animals ,Humans ,Pyrroles ,Protein Kinase Inhibitors ,Pharmacology ,Ovarian Neoplasms ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Cancer ,General Medicine ,Neoplasms, Experimental ,medicine.disease ,Intracellular signal transduction ,Pyrimidines ,Tumor progression ,Drug Design ,Focal Adhesion Kinase 1 ,Indans ,Cancer research ,Microsomes, Liver ,Female ,Drug Screening Assays, Antitumor ,Ovarian cancer - Abstract
Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy. Structure–activity relationship (SAR) exploration identified 36 as a potent FAK inhibitor, which exhibited inhibitory activities against FAK signaling in vitro. Treatment with 36 not only decreased migration and invasion of PA-1 cells, but also reduced expression of MMP-2 and MMP-9. Moreover, 36 inhibited tumor growth and metastasis, and no obvious adverse effects were observed during the in vivo study. These results revealed the potential of FAK inhibitor 36 for treatment of ovarian cancer.
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- 2021
6. Nifuroxazide Ameliorates Pulmonary Fibrosis By Blocking Myofibroblast Genesis And Stat3 Activation: A Drug Repurposing Study
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Yuqin Yao, Hongyao Liu, Guan Wang, Liang Ouyang, Liqun Wang, Zui Tan, Cailing Gan, Wenya Yin, Qianyu Zhang, Yali Li, Tinghong Ye, Luoting Yu, and Yongmei Xie
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Stat3 activation ,Drug repositioning ,Blocking (radio) ,business.industry ,Pulmonary fibrosis ,Cancer research ,medicine ,medicine.disease ,business ,Myofibroblast ,Nifuroxazide ,medicine.drug - Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a lung disease with complex pathogenesis, high mortality. The development of new drugs is time-consuming and laborious, and the research on new use of old drugs can save time and clinical costs and even avoid serious side effects. Nifuroxazide (NIF) was originally used to treat diarrhoea, but in recent years it has been found to have other pharmacological effects such as anti-tumor and inhibiting inflammatory diseases related to diabetic nephropathy. However, there are no reports about its role in pulmonary fibrosis.Methods: The therapeutic effect of NIF on bleomycin (BLM)-induced pulmonary fibrosis in vivo was measured by ELISA, hydroxyproline content, H&E and Masson staining, IHC and Western blot. The content of immune cells in lung tissue was analyzed by flow cytometry. NIF cytotoxicity were evaluated in NIH/3T3, Human pulmonary fibroblasts (HPF), A549 and Rat primary lung fibroblasts (RPLF) using MTT assay. Finally, a cell model induced by transforming growth factor-β1 (TGF-β1) stimulation and different in vitro experiments (Immunofluorescence, Western blot, Wound migration assay) were conducted to determine the effect of NIF on the activation of fibroblasts and the epithelial-mesenchymal transition (EMT) and migration of epithelial cells.Results: In vivo, intraperitoneal injection of NIF relieved and reversed pulmonary fibrosis caused by BLM bronchial instillation. In addition, nifuroxazide inhibited the expression of a variety of cellular inflammatory factors and immune cells. Furthermore, nifuroxazide suppressed the activation of fibroblasts and the EMT of epithelial cells induced by TGF-β1. Most importantly, we used an analytical docking experiment and thermal shift assay to further verify that nifuroxazide worked in conjunction with Stat3. Moreover, nifuroxazide decreased the expression of p-Stat3 in vitro and in vivo.Conclusion: These results suggest that NIF inhibits and reverses pulmonary fibrosis and support NIF as a viable treatment option that may bring benefits to patients with IPF.
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- 2021
7. A novel multikinase inhibitor SKLB‐YTH‐60 ameliorates inflammation and fibrosis in bleomycin‐induced lung fibrosis mouse models
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Liqun Wang, Hongyao Liu, Yuqin Yao, Xiuli Wu, Tinghong Ye, Wei Wei, Qianyu Zhang, Zui Tan, Xingping Su, Luoting Yu, Zhihao Liu, Liang Ouyang, Lin Yue, Guan Wang, and Cailing Gan
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Male ,0301 basic medicine ,Epithelial-Mesenchymal Transition ,Pulmonary Fibrosis ,YTH‐60 ,Inflammation ,Bleomycin ,Rats, Sprague-Dawley ,Transforming Growth Factor beta1 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,immune cells ,0302 clinical medicine ,Immune system ,Fibrosis ,Pulmonary fibrosis ,Animals ,Humans ,Medicine ,Epithelial–mesenchymal transition ,Protein Kinase Inhibitors ,Cell Proliferation ,A549 cell ,epithelial‐mesenchymal transition ,Binding Sites ,business.industry ,Original Articles ,Cell Biology ,General Medicine ,medicine.disease ,Rats ,Mice, Inbred C57BL ,Molecular Docking Simulation ,Disease Models, Animal ,030104 developmental biology ,chemistry ,A549 Cells ,Drug Design ,030220 oncology & carcinogenesis ,Cancer research ,Original Article ,medicine.symptom ,multikinase inhibitor ,business ,Half-Life - Abstract
Objectives Idiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis. Materials and Methods SKLB‐YTH‐60 was developed through computer‐aided drug design, de novo synthesis and high‐throughput screening. We employed the bleomycin (BLM)‐induced lung fibrosis animal models and used TGF‐β1 to induce the epithelial‐mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α‐smooth muscle actin (α‐SMA), E‐cadherin, p‐FGFR1, p‐PLCγ, p‐Smad2/3 and p‐Erk1/2 was detected by western blot. Results YTH‐60 has obvious anti‐proliferative activity on fibroblasts and A549 cells. Moreover, YTH‐60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF‐β/Smad‐dependent pathways. Intraperitoneal administration of preventive YTH‐60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH‐60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH‐60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half‐life time (T 1/2 = 8.03 hours). Conclusions Taken together, these preclinical evaluations suggested that YTH‐60 could be a promising drug candidate for treating IPF., Schematic model for anti‐fibrotic activity of SKLB‐YTH‐60. In vitro YTH‐60 inhibits the activation of fibroblasts and the EMT of epithelial cells induced by TGFβ1. Intraperitoneal injection of YTH‐60 not only inhibits the bleomycin‐induced lung inflammation, regulates the lung immune microenvironment, but also prevents and reverses pulmonary fibrosis. Finally, the anti‐fibrosis effect of YTH‐60 may be via inhibiting of FGFR and TGF‐β/Smad signaling pathway.
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- 2021
8. Structure-guided discovery of novel potent and efficacious proteolysis targeting chimera (PROTAC) degrader of BRD4
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Jing Ren, Yao-Jie Shi, Qiwei Wang, Luoting Yu, Wang Xiang, and Kai Ran
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BRD4 ,Large molecular weight ,Pyridones ,Proteolysis ,Antineoplastic Agents ,Cell Cycle Proteins ,Biochemistry ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Molecular Biology ,Cell Proliferation ,Sulfonamides ,medicine.diagnostic_test ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Proteolysis targeting chimera ,In vitro ,Cell culture ,Drug Screening Assays, Antitumor ,Transcription Factors - Abstract
Bromodomain-containing protein 4 (BRD4) has been identified as a potential target in the treatment of many cancers and several BRD4 inhibitors have entered clinical studies. Previous studies have shown that BRD4 degraders have potential to overcome resistance to BRD4 inhibitors. However, most of the BRD4 degraders have poor solubility and bioavailability, one of which the reason is large molecular weight. Here, we describe the design, synthesis, and evaluation studies of a BRD4 degrader based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have led to the discovery of compound 15, which is a weak inhibitor and potent BRD4 degrader with a molecular weight of 821.8. In vitro, 15 can completely degrade BRD4 at nanomolar concentration, with DC50 = 0.25 and 3.15 nM in MV4-11 and RS4-11 cell lines, respectively. Further optimization of compound 15 may reduce its molecular weight and improve druggabillity, and provide a new choice for the treatment of cancer.
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- 2021
9. Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents
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Li Jian, Luo Wei, Kun-Lin Liu, Chao Gao, Huang Zhigang, Luoting Yu, Cui-Ting Peng, Chen Shuhui, Tao Xin, and Charles Z. Ding
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Drug ,Cell Survival ,medicine.drug_class ,media_common.quotation_subject ,Clinical Biochemistry ,Antitubercular Agents ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Antimycobacterial ,01 natural sciences ,Biochemistry ,Permeability ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Chlorocebus aethiops ,Drug Discovery ,medicine ,Animals ,Cytotoxicity ,Oxazoles ,Vero Cells ,Molecular Biology ,media_common ,010405 organic chemistry ,Organic Chemistry ,Mycobacterium tuberculosis ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Solubility ,chemistry ,Nitroimidazoles ,Molecular Medicine ,Piperidine ,Delamanid ,Linker ,medicine.drug - Abstract
New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.
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- 2019
10. Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis
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Cui-Ting Peng, Zhanzhan Feng, Xi Yu, Ying Xu, Hualong He, Jun Zeng, Xuejiao Song, Luoting Yu, Xi Hu, Quan-Fang Hu, Weiqiong Zuo, Zhihao Liu, Tiantao Gao, and Qian Lei
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0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Lung Neoplasms ,Cell Survival ,MAP Kinase Signaling System ,p38 mitogen-activated protein kinases ,Cell ,Administration, Oral ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein kinase A ,Protein Kinase Inhibitors ,Cell Proliferation ,Mitogen-Activated Protein Kinase Kinases ,Chemistry ,Kinase ,Cell Cycle ,Cell cycle ,HCT116 Cells ,Xenograft Model Antitumor Assays ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Signal transduction ,Colorectal Neoplasms ,Proto-oncogene tyrosine-protein kinase Src - Abstract
The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell–originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy. Here, we report the development of a TOPK selective inhibitor SKLB-C05, with subnanomolar inhibitory potency. In vitro, SKLB-C05 exhibited excellent cytotoxicity and anti-migration and invasion activity on TOPK high-expressing CRC cells and induced cell apoptosis. These activities could attribute to its inhibition of TOPK downstream signaling including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1, 2, and 3 (JNK1/2/3), as well as downregulation of FAK/Src- MMP signaling. Furthermore, SKLB-C05 disrupted cell mitosis and blocked CRC cell cycle. In vivo, oral administration of SKLB-C05 at concentrations of 20 and 10 mg kg−1·day−1 dramatically attenuated CRC tumor xenograft growth and completely suppressed hepatic metastasis of HCT116 cells, respectively. Thus, these findings suggest that SKLB-C05 is a specific TOPK inhibitor with potent anti-CRC oncogenic activity in vitro and in vivo.
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- 2019
11. Design, synthesis and biological evaluation of novel 1-phenyl phenanthridin-6(5H)-one derivatives as anti-tumor agents targeting TOPK
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Yao-Jie Shi, Tiantao Gao, Quan-Fang Hu, Luoting Yu, Qian Lei, Qiang Feng, Zhihao Liu, and Zhen-Jia Chen
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Colorectal cancer ,Antineoplastic Agents ,Apoptosis ,Quinolones ,01 natural sciences ,Mice ,03 medical and health sciences ,Pharmacokinetics ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Protein kinase A ,030304 developmental biology ,Mitogen-Activated Protein Kinase Kinases ,Pharmacology ,0303 health sciences ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Cancer ,General Medicine ,Phenanthrenes ,medicine.disease ,Xenograft Model Antitumor Assays ,Phenanthridines ,0104 chemical sciences ,Bioavailability ,Cancer cell ,Cancer research ,Heterografts ,Colorectal Neoplasms - Abstract
T–lymphokine-activated killer cell–originated protein kinase (TOPK) is a serine-threonine mitogen-activated protein kinase that is highly expressed in many types of human cancer. Due to its important role in cancer progression, TOPK is becoming an attractive target in chemotherapeutic drug design. In this study, a series of 1-phenyl phenanthridin-6(5H)-one derivatives have been identified as a novel chemical class of TOPK inhibitors. Some of them displayed very potent anti-cancer activity with IC50s less than 100 nM, superior than reference compound OTS964. The most potent compound, 9g suppressed the growth of cancer cells by apoptosis and specifically inhibited the activities of TOPK. Oral administration of 9g effectively suppressed tumor growth with TGI >79.7% in colorectal cancer xenograft models, demonstrating superior efficacy compared to OTS964. Pharmacokinetic studies reveal its good oral bioavailability. Our findings therefore show that 9g is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic agent against colorectal cancer.
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- 2019
12. YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect
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Tiantao Gao, Cui-Ting Peng, Zhongping Li, Zhanzhan Feng, Tinghong Ye, Wei Wei, Ningyu Wang, Lu Xiong, Yong Xia, Xuejiao Song, Luoting Yu, Zhihao Liu, and Qian Lei
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0301 basic medicine ,Cancer Research ,Drug Evaluation, Preclinical ,0302 clinical medicine ,Acetamides ,Medicine ,RNA, Small Interfering ,Centrioles ,Kinase ,lcsh:Cytology ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Molecular Docking Simulation ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Female ,Signal transduction ,Signal Transduction ,Cyclin-Dependent Kinase Inhibitor p21 ,PLK4 ,Indazoles ,Immunology ,Mitosis ,Antineoplastic Agents ,Breast Neoplasms ,Protein Serine-Threonine Kinases ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,In vivo ,Cell Line, Tumor ,CDC2 Protein Kinase ,Humans ,cdc25 Phosphatases ,lcsh:QH573-671 ,Protein Kinase Inhibitors ,Cell Proliferation ,business.industry ,Cancer ,Cell Biology ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Pyrimidines ,030104 developmental biology ,Apoptosis ,Cell culture ,Cancer research ,business - Abstract
Polo-like kinase 4 (PLK4) is indispensable for precise control of centriole duplication. Abnormal expression of PLK4 has been reported in many human cancers, and inhibition of PLK4 activity results in their mitotic arrest and apoptosis. Therefore, PLK4 may be a valid therapeutic target for antitumor therapy. However, clinically available small-molecule inhibitors targeting PLK4 are deficient and their underlying mechanisms still remain not fully clear. Herein, the effects of YLT-11 on breast cancer cells and the associated mechanism were investigated. In vitro, YLT-11 exhibited significant antiproliferation activities against breast cancer cells. Meanwhile, cells treated with YLT-11 exhibited effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication and mitotic defects, sequentially making tumor cells more vulnerable to chemotherapy. Furthermore, YLT-11 could strongly regulate downstream factors of PLK4, which was involved in cell cycle regulation, ultimately inducing apoptosis of breast cancer cell. In vivo, oral administration of YLT-11 significantly suppressed the tumor growth in human breast cancer xenograft models at doses that are well tolerated. In summary, the preclinical data show that YLT-11 could be a promising candidate drug for breast tumor therapy.
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- 2018
13. Design, synthesis and biological evaluations of a series of Pyrido[1,2-a]pyrimidinone derivatives as novel selective FGFR inhibitors
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Zhanzhan Feng, Jun Zeng, Wei Wei, Wang Xiang, Kai Ran, Xiang Hu, Ning-Yu Wang, Xiaojie He, Luoting Yu, Zhihao Liu, and Guoquan Wan
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Cell cycle checkpoint ,Antineoplastic Agents ,Apoptosis ,Mice, SCID ,Pyrimidinones ,medicine.disease_cause ,01 natural sciences ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Erdafitinib ,Mice, Inbred NOD ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 2 ,Protein Kinase Inhibitors ,030304 developmental biology ,Cell Proliferation ,Pharmacology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Kinase ,Chemistry ,Organic Chemistry ,Cell Cycle ,General Medicine ,Neoplasms, Experimental ,0104 chemical sciences ,Fibroblast growth factor receptor ,Drug Design ,Cancer research ,Phosphorylation ,Female ,Signal transduction ,Drug Screening Assays, Antitumor ,Carcinogenesis - Abstract
Aberrant signaling of fibroblast growth factor receptors (FGFRs) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFRs a compelling target for anticancer therapy. Herein, we describe the design and synthesis of pyrido[1,2-a]pyrimidinone derivatives as potent FGFR inhibitors. Examination of structure–activity relationships and preliminary assessment identified 23d as a novel FGFR inhibitor that displayed excellent potency in vitro. Candidate 23d suppressed the phosphorylation of FGFR signaling pathways and induced cell cycle arrest and apoptosis at low nanomolar concentration. In the kinase inhibition profile, 23d showed excellent kinase selectivity for the FGFR family. Furthermore, 23d showed higher aqueous solubility than Erdafitinib. Moreover, 23d exhibited potent antitumor activity (tumor growth inhibition = 106.4%) in FGFR2-amplified SNU-16 gastric cancer xenograft model using a daily oral dose of 30 mg/kg. These results suggest that 23d is a promising candidate for further drug development.
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- 2021
14. Synthesis and Biological Evaluation of Novel 4-(4-Formamidophenylamino)
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Yong Xia, Luoting Yu, Xiu-Xiu Zeng, Nana Meng, Youzhi Xu, Shuyan Zhou, and Min Hu
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Necrosis ,Angiogenesis ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,anti-proliferation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,lcsh:Organic chemistry ,In vivo ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Physical and Theoretical Chemistry ,4-(4-formamidophenylamino)-N-methylpicolinamide derivatives ,Picolinic Acids ,030304 developmental biology ,Biological evaluation ,Cell Proliferation ,0303 health sciences ,Mice, Inbred BALB C ,Chemistry ,Organic Chemistry ,angiogenesis inhibitors ,Neoplasms, Experimental ,In vitro ,Chemistry (miscellaneous) ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Molecular Medicine ,Female ,pharmacology ,medicine.symptom ,Drug Screening Assays, Antitumor - Abstract
A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.
- Published
- 2021
15. YLZ-F5, a novel polo-like kinase 4 inhibitor, inhibits human ovarian cancer cell growth by inducing apoptosis and mitotic defects
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Junxiang Su, Luoting Yu, Zhihao Liu, Meiqin Yang, Yongxia Zhu, Zhaodi Wang, Yue Wang, Xiaoyi Li, Jun Zeng, Yanling Qu, and Xueqin Wang
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0301 basic medicine ,Cancer Research ,Indazoles ,Mitosis ,Antineoplastic Agents ,Apoptosis ,Polo-like kinase ,Protein Serine-Threonine Kinases ,Toxicology ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Pharmacology (medical) ,Centrosome duplication ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Proliferation ,Centrioles ,Pharmacology ,Ovarian Neoplasms ,Cell growth ,Chemistry ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Female ,Ovarian cancer ,Multipolar spindles ,Cytokinesis - Abstract
Polo-like kinase 4 (PLK4), a member of the polo-like kinase family, plays several important roles in mitotic regulation, including centrosome duplication, spindle formation, and cytokinesis. PLK4 overexpression is frequently detected in many human cancers, including ovarian cancer, and the inhibition of PLK4 activity results in cancer cell mitotic arrest and apoptosis. Therefore, PLK4 might be a valid therapeutic target for antitumor therapy. In the present study, we aimed to determine if YLZ-F5, a potent small-molecule inhibitor of PLK4, inhibits ovarian cancer cell growth. MTT assay showed that YLZ-F5 inhibited ovarian cancer cell proliferation in a concentration- and time-dependent manner. The results of colony formation assays were consistent with those of the MTT assay results. In addition, YLZ-F5 induced ovarian cancer cell apoptosis that was associated with activation of caspase-3/caspase-9. Moreover, YLZ-F5 caused aberrant in centriole duplication that was associated with the inhibition of PLK4 phosphorylation. Notably, we showed that YLZ-F5 promoted the accumulation of ovarian cancer cells with mitotic defects (> 4 N DNA content) in a concentration-dependent manner. Furthermore, YLZ-F5 markedly inhibited the migration of A2780 cells. Taken together, these findings suggest that YLZ-F5 is a potential drug candidate for human ovarian cancer.
- Published
- 2020
16. Preclinical Evaluation of Amphihevir, a First-in-Class Clinical Hepatitis C Virus NS4B Inhibitor
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Luoting Yu, Fu Zhifei, Lichun Wang, Zhengxian Gu, Wang Jianfei, Ning-Yu Wang, Yang Zhang, Chen Shuhui, and Tao Xin
- Subjects
Pharmacology ,0303 health sciences ,NS3 ,030306 microbiology ,business.industry ,viruses ,Hepatitis C virus ,Hepatitis C ,Drug resistance ,medicine.disease_cause ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,Infectious Diseases ,Pharmacokinetics ,chemistry ,Medicine ,Potency ,Pharmacology (medical) ,NS5A ,business ,NS5B ,030304 developmental biology - Abstract
Amphihevir, a benzofuran derivative, is the first reported hepatitis C virus (HCV) nonstructural protein 4B (NS4B) inhibitor that has advanced to clinical trials (currently in phase Ib trial [CTR20170632]). Here, we report the results of a preclinical study of its potency, toxicity, selectivity, drug metabolism and pharmacokinetics (DMPK), and safety profiles. Amphihevir displayed good antiviral activities against genotype 1a (50% effective concentration [EC(50)] of 0.34 nM) and genotype 1b (EC(50) of 1.97 nM) replicons and no cytotoxicity in 12 cell lines derived from animals and humans. Amphihevir was found to be inactive against other viruses, human kinases, and G protein-coupled receptors (GPCRs), which implies its good selectivity. A 9-day long-term treatment of genotype 1b replicons with amphihevir resulted in a 3.8 Log(10) decline of the hepatitis C viral RNA at a concentration of 25× EC(90). Drug resistance screening showed that mutations occurred at H94, F98, and V105 of NS4B, which mediated the resistance to amphihevir. This result suggests that NS4B is the main target of amphihevir. There was no cross-resistance between amphihevir and NS5A, NS3/4A, and NS5B inhibitors, suggesting that amphihevir in combination with other anti-hepatitis C virus drugs could be used to treat hepatitis C, as proven by studies of amphihevir and other hepatitis C virus inhibitors. Pharmacokinetic studies demonstrated that amphihevir has good oral bioavailability and appropriate half-life (t(1/2)) in rats and dogs, thereby supporting its use once per day. Finally, amphihevir showed good safety profiles in rats and dogs. The results shed light on the use of amphihevir as a potential treatment option for chronic hepatitis C patients.
- Published
- 2019
17. Structural and functional studies on Pseudomonas aeruginosa DspI: implications for its role in DSF biosynthesis
- Author
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Li-Hui He, Zhenling Wang, Mao Lian, Xingjun Cheng, Tinghong Ye, Yi-Bo Zhu, Ning-Yu Wang, Ying-Jie Song, Cui-Ting Peng, Tao Li, Luoting Yu, Si-Min Ju, Rui Bao, Chang-Cheng Li, Li Liu, and Qing-Jie Xiao
- Subjects
0301 basic medicine ,Models, Molecular ,Protein Conformation ,Virulence ,Swarming motility ,Sequence Homology ,lcsh:Medicine ,Isomerase ,medicine.disease_cause ,Article ,Gene Expression Regulation, Enzymologic ,Diffusion ,Fatty Acids, Monounsaturated ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Biosynthesis ,Bacterial Proteins ,Cell Movement ,medicine ,Amino Acid Sequence ,Author Correction ,lcsh:Science ,Enoyl-CoA Hydratase ,Multidisciplinary ,Pyoverdine ,Pseudomonas aeruginosa ,Chemistry ,lcsh:R ,Biofilm ,Quorum Sensing ,Quorum sensing ,030104 developmental biology ,Biochemistry ,Flagella ,Biofilms ,Fimbriae, Bacterial ,lcsh:Q ,Signal Transduction - Abstract
DspI, a putative enoyl-coenzyme A (CoA) hydratase/isomerase, was proposed to be involved in the synthesis of cis-2-decenoic acid (CDA), a quorum sensing (QS) signal molecule in the pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study provided a structural basis for the dehydration reaction mechanism of DspI during CDA synthesis. Structural analysis reveals that Glu126, Glu146, Cys127, Cys131 and Cys154 are important for its enzymatic function. Moreover, we show that the deletion of dspI results in a remarkable decreased in the pyoverdine production, flagella-dependent swarming motility, and biofilm dispersion as well as attenuated virulence in P. aeruginosa PA14. This study thus unravels the mechanism of DspI in diffusible signal factor (DSF) CDA biosynthesis, providing vital information for developing inhibitors that interfere with DSF associated pathogenicity in P. aeruginosa.
- Published
- 2018
18. A novel benzothiazinethione analogue SKLB-TB1001 displays potent antimycobacterial activities in a series of murine models
- Author
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Chao Gao, Lu Xiong, Luoting Yu, Xiu-Xiu Zeng, Yuquan Wei, Ningyu Wang, Cui-Ting Peng, Kai Ran, Yao-Jie Shi, Lidan Zhang, Xin-Yu You, and Tinghong Ye
- Subjects
0301 basic medicine ,Tuberculosis ,medicine.drug_class ,030106 microbiology ,Antitubercular Agents ,Colony Count, Microbial ,Pharmacology ,Antimycobacterial ,Mycobacterium tuberculosis ,03 medical and health sciences ,Thiadiazoles ,Animals ,Medicine ,Lung ,Histological examination ,Colony-forming unit ,Mice, Inbred BALB C ,Mycobacterium bovis ,biology ,business.industry ,Isoniazid ,General Medicine ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Virology ,Mice, Inbred C57BL ,Disease Models, Animal ,Treatment Outcome ,030104 developmental biology ,Streptomycin ,Female ,business ,medicine.drug - Abstract
New chemotherapeutic compounds and regimens are needed to combat multidrug-resistant Mycobacterium tuberculosis. Here, we used a series of murine models to assess an antitubercular lead compound SKLB-TB1001. In the Mycobacterium bovis bacillus Calmette-Guérin and the acute M. tuberculosis H37Rv infection mouse models, SKLB-TB1001 significantly attenuated the mycobacterial load in lungs and spleens. The colony forming unit counts and histological examination of lungs from H37Rv infected mice revealed that the benzothiazinethione analogue SKLB-TB1001 as a higher dose level was as effective as isoniazid. Moreover, in a multidrug-resistant (MDR)-TB mouse model, SKLB-TB1001 showed significant activity in a dose-dependent manner and was more effective than streptomycin. These results suggested that SKLB-TB1001 could be an antitubercular drug candidate worth further investigation.
- Published
- 2017
19. Synthesis and biological evaluation of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as PLK4 inhibitors for the treatment of breast cancer
- Author
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Guoyi Yan, Tinghong Ye, Chao Gao, Luoting Yu, Zhihao Liu, Qian Lei, Lu Xiong, Ningyu Wang, Yao-Jie Shi, and Wei Wei
- Subjects
0301 basic medicine ,PLK4 ,Chemistry ,Kinase ,General Chemical Engineering ,Regulator ,General Chemistry ,medicine.disease_cause ,In vitro ,03 medical and health sciences ,030104 developmental biology ,Apoptosis ,medicine ,Cancer research ,Centriole replication ,Carcinogenesis ,Mitosis - Abstract
Polo-like kinase 4 (PLK4), a vital regulator of centriole duplication, is important for maintaining genome stability. Dysregulation of PLK4 has been found in several human cancers and is associated with a predisposition to tumorigenesis. Herein, we describe the discovery of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as potent PLK4 inhibitors with more concise structure using a scaffold hopping strategy. SAR exploration and preliminary assessment identified 14i as a new PLK4 inhibitor which displayed excellent potency in vitro. 14i could inhibit the activity of PLK4, perturb centriole replication, result in mitosis disorder and induce cell apoptosis in breast cancer cells. Moreover 14i demonstrated significant antitumor efficacy in the MDA-MB-468 and MDA-MB-231 xenograft models. This study suggested that this concise chemotype would represent a promising scaffold of PLK4 inhibitors for cancer therapy and 14i would be an attractive lead compound for further optimization and evaluation.
- Published
- 2017
20. Small Molecule TH-39 Potentially Targets Hec1/Nek2 Interaction and Exhibits Antitumor Efficacy in K562 Cells via G0/G1 Cell Cycle Arrest and Apoptosis Induction
- Author
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Chao Gao, Li Liu, Yong Luo, Lidan Zhang, Luoting Yu, Zhihao Liu, Ningyu Wang, Wei Wei, Tinghong Ye, and Yongxia Zhu
- Subjects
0301 basic medicine ,Cell Survival ,Physiology ,Antineoplastic Agents ,Cell Cycle Proteins ,Apoptosis ,Biology ,Resting Phase, Cell Cycle ,lcsh:Physiology ,Flow cytometry ,Small Molecule Libraries ,lcsh:Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,NIMA-Related Kinases ,MTT assay ,TH-39 ,lcsh:QD415-436 ,Cell Shape ,K562 cells ,chemistry.chemical_classification ,Reactive oxygen species ,medicine.diagnostic_test ,lcsh:QP1-981 ,Cell growth ,Nuclear Proteins ,Myeloid leukemia ,Hydrogen-Ion Concentration ,G1 Phase Cell Cycle Checkpoints ,Cell biology ,Cytoskeletal Proteins ,Thiazoles ,030104 developmental biology ,Hec1/Nek2 ,chemistry ,Cinnamates ,030220 oncology & carcinogenesis ,Cancer research ,Reactive Oxygen Species ,G1 phase ,Protein Binding ,G0/G1 cell cycle arrest - Abstract
Background: Cancer is still a major public health issue worldwide, and new therapeutics with anti-tumor activity are still urgently needed. Methods: The anti-tumor activity of TH-39, which shows potent anti-proliferative activity against K562 cells with an IC50 of 0.78 µM, was investigated using immunoblot, co-immunoprecipitation, the MTT assay, and flow cytometry. Results: Mechanistically, TH-39 may disrupt the interaction between Hec1 and Nek2 in K562 cells. Moreover, TH-39 inhibited cell proliferation in a concentration- and time-dependent manner by influencing the morphology of K562 cells and inducing G0/G1 phase arrest. G0/G1 phase arrest was associated with down-regulation of CDK2-cyclin E complex and CDK4/6-cyclin D complex activities. Furthermore, TH-39 also induced cell apoptosis, which was associated with activation of caspase-3, down-regulation of Bcl-2 expression and up-regulation of Bax. TH-39 could also decrease mitochondrial membrane potential (Δψm) and increase reactive oxygen species (ROS) accumulation in K562 cells. The results indicated that TH-39 might induce apoptosis via the ROS-mitochondrial apoptotic pathway. Conclusion: This study highlights the potential therapeutic efficacy of the anti-cancer compound TH-39 in treatment-resistant chronic myeloid leukemia.
- Published
- 2016
21. Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors
- Author
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Xi Hu, Luoting Yu, Fei Teng, Zhihao Liu, Zhanzhan Feng, Qiang Feng, Hualong He, and Qiangsheng Zhang
- Subjects
Protein subunit ,Clinical Biochemistry ,Pharmaceutical Science ,Apoptosis ,macromolecular substances ,01 natural sciences ,Biochemistry ,Methylation ,Metastasis ,Epigenesis, Genetic ,Histones ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Stilbenes ,medicine ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Enzyme Inhibitors ,Molecular Biology ,Psychological repression ,Cell Proliferation ,biology ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,EZH2 ,medicine.disease ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Cell culture ,Drug Design ,biology.protein ,Cancer research ,Molecular Medicine ,Drug Screening Assays, Antitumor ,PRC2 ,Lead compound - Abstract
Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the “tail” region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2WT IC50 = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC50 = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.
- Published
- 2019
22. Novel Dual BET and PLK1 Inhibitor WNY0824 Exerts Potent Antitumor Effects in CRPC by Inhibiting Transcription Factor Function and Inducing Mitotic Abnormality
- Author
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Jun Zeng, Weiqiong Zuo, Luoting Yu, Zhanzhan Feng, Zhihao Liu, Tiantao Gao, Xi Hu, Ning-Yu Wang, Qianqian Wang, Lifeng Zhao, Kun-Jie Xiao, Ying Xu, and Xuejiao Song
- Subjects
0301 basic medicine ,Male ,Cancer Research ,BRD4 ,Mitosis ,Antineoplastic Agents ,Apoptosis ,Cell Cycle Proteins ,Mice, SCID ,Protein Serine-Threonine Kinases ,urologic and male genital diseases ,PLK1 ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,Mice ,0302 clinical medicine ,In vivo ,Mice, Inbred NOD ,Proto-Oncogene Proteins ,Nitriles ,Phenylthiohydantoin ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Enzalutamide ,Animals ,Humans ,Transcription factor ,Cell Cycle ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Benzamides ,Cancer research ,Transcription Factors - Abstract
Castration-resistant prostate cancer (CRPC) is a lethal disease with few treatment alternatives once patients become resistant to second-generation antiandrogens. In CRPC, BET proteins are key regulators of AR- and MYC-mediated transcription, while the PLK1 inhibitor potentially downregulates AR and MYC besides influencing the cell cycle. Therefore, synchronous inhibition of BET and PLK1 would be a promising approach for CRPC therapy. This study developed a dual BET and PLK1 inhibitor WNY0824 with nanomolar and equipotent inhibition of BRD4 and PLK1. In vitro, WNY0824 exhibited excellent antiproliferation activity on AR-positive CRPC cells and induced apoptosis. These activities are attributable to its disruption of the AR-transcriptional program and the inhibition of the ETS pathway. Furthermore, WNY0824 downregulated MYC and induced mitotic abnormality. In vivo, oral WNY0824 administration suppressed tumor growth in the CRPC xenograft model of enzalutamide resistance. These findings suggest that WNY0824 is a selective dual BET and PLK1 inhibitor with potent anti-CRPC oncogenic activity and provides insights into the development of other novel dual BET- and PLK1-inhibiting drugs.
- Published
- 2019
23. Natural product pectolinarigenin exhibits potent anti-metastatic activity in colorectal carcinoma cells in vitro and in vivo
- Author
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Yan Yu, Cailing Gan, Xi Yu, Hongyao Liu, Luoting Yu, Yali Li, Tinghong Ye, Wenya Yin, and Qianyu Zhang
- Subjects
STAT3 Transcription Factor ,Clinical Biochemistry ,Pharmaceutical Science ,Down-Regulation ,Antineoplastic Agents ,Apoptosis ,01 natural sciences ,Biochemistry ,Metastasis ,In vivo ,Cell Movement ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Viability assay ,Neoplasm Metastasis ,Molecular Biology ,Cell Proliferation ,Mice, Inbred BALB C ,010405 organic chemistry ,Chemistry ,Myeloid-Derived Suppressor Cells ,Organic Chemistry ,Cell migration ,medicine.disease ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Matrix Metalloproteinase 9 ,Chromones ,Cancer cell ,Cancer research ,Molecular Medicine ,Female ,Colorectal Neoplasms ,CD8 - Abstract
Colorectal carcinoma (CRC) is one of the most common cancers with high metastatic potential, explaining why identifying new drug candidates that inhibit tumour metastasis is an urgent need. The aim of this study was to evaluate the biological activities of pectolinarigenin (PEC, a natural flavonoid present in Cirsium chanroenicum) in CRC in vitro and in vivo and to determine its underlying mechanism of action. Here, we observed that treatment with PEC could inhibit cell viability and induce apoptosis in cancer cells in a concentration- and time-dependent manner. The occurrence of apoptosis was associated with activation of caspase-3 and Bax and decreased expression of Bcl-2. In addition, PEC markedly impaired CRC cell migration and invasion by downregulating the expression of matrix metalloproteinase (MMP-9) and phosphorylated-Stat3Tyr705. Moreover, our studies showed that PEC inhibited abdominal metastasis models of murine colorectal cancer. In addition, histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, MMP9-positive cells and p-Stat3Tyr705 cells upon treatment with PEC compared to control samples. Furthermore, PEC reduced the number of myeloid-derived suppressor cells (MDSCs) in the blood and tumours, which was accompanied by the increased infiltration of CD8+T cells in the blood. Taken together, our findings suggested that PEC could be used as a natural drug to inhibit CRC metastasis.
- Published
- 2019
24. Synthesis and biological evaluation of (1,2,4)triazole[4,3-a]pyridine derivatives as potential therapeutic agents for concanavalin A-induced hepatitis
- Author
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Quan-Fang Hu, Luoting Yu, Mengyi Shen, Zhihao Liu, Tinghong Ye, Yong Xia, Qianqian Wang, Xiaoli Fan, Jing Ren, Ning-Yu Wang, Yao-Jie Shi, Juan Rong, and Xuejiao Song
- Subjects
Lipopolysaccharides ,Lipopolysaccharide ,medicine.drug_class ,Cell Survival ,Pyridines ,Aspartate transaminase ,Autoimmune hepatitis ,Pharmacology ,Nitric Oxide ,01 natural sciences ,Anti-inflammatory ,Flow cytometry ,Hepatitis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Concanavalin A ,Animals ,Humans ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Mice, Inbred BALB C ,biology ,medicine.diagnostic_test ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,General Medicine ,Triazoles ,medicine.disease ,0104 chemical sciences ,Disease Models, Animal ,RAW 264.7 Cells ,Alanine transaminase ,chemistry ,Drug Design ,biology.protein ,Female - Abstract
A series of (1,2,4)triazole[4,3-a]pyridine (TZP) derivatives have been designed and synthesized. Compound 8d was identified as having the most potent inhibitory activity on NO release in response to lipopolysaccharide (LPS) stimulation and inhibition of the migration induced by MCP-1 protein on RAW264.7 macrophages. Based on the screening data, an immunofluorescence assay and a real-time qPCR assay were conducted, indicating that compound 8d suppressed NF-κB p65 translocation and expression of inflammatory genes by concanavalin A (Con A)-induced RAW264.7 macrophages. More importantly, 8d also exhibited potent efficacy, alleviating Con A-induced hepatitis by downregulating the levels of plasma alanine transaminase (ALT), aspartate transaminase (AST) and inflammatory infiltration in a mouse autoimmune hepatitis (AIH) model. In addition, the flow cytometry (FCM) data showed that compound 8d inhibited the accumulation of MDSCs in the liver of Con A-induced mice. These findings raise the possibility that compound 8d might serve as a potential agent for the treatment of AIH.
- Published
- 2019
25. Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux
- Author
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Huizhi Xi, Yao Xie, Meiping Xiong, Hao Yang, Tinghong Ye, Luoting Yu, Wentao Lin, Yong Xia, Fuyan Xu, and Qiang Xue
- Subjects
0301 basic medicine ,Autophagosome ,Lung Neoplasms ,Skin Neoplasms ,Cell Survival ,medicine.medical_treatment ,Antineoplastic Agents ,Bone Neoplasms ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Autophagy ,medicine ,Animals ,Humans ,Melanoma ,Membrane Potential, Mitochondrial ,Pharmacology ,LAMP1 ,Brain Neoplasms ,business.industry ,Cell Cycle ,Drug Repositioning ,Bone metastasis ,Immunotherapy ,medicine.disease ,Trifluoperazine ,Mice, Inbred C57BL ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Antipsychotic Agents ,Brain metastasis - Abstract
Targeted therapies and immunotherapy have brought substantial benefits to patients with melanoma. However, brain metastases remain the biggest threat to the survival and quality of life of melanoma patients. One of the major challenges to an effective therapy is the inability of drugs to penetrate the blood-brain barrier (BBB). Anti-schizophrenic drugs can cross the BBB, and many of them have demonstrated anti-cancer effects. Repurposing existing drugs for new clinical indications is an alluring strategy for anticancer drug discovery. Herein, we applied this strategy and screened a small collection of existing anti-schizophrenic drugs to use as anti-melanoma agents. Among them, trifluoperazine dihydrochloride (TFP) exhibited promising potencies for suppressing the growth and metastasis of melanoma, both in vitro and in vivo. TFP obviously suppressed the viability of melanoma cells within the micromolar range and inhibited the growth of melanoma in the subcutaneous mice models. Notably, intraperitoneal (i.p.) administration of TFP (40 mg/kg/day) obviously inhibited the growth of intra-carotid-injection established melanoma brain metastasis and extended the survival of brain metastasis-bearing mice. Moreover, TFP significantly suppressed lung metastasis and bone metastasis of melanoma in preclinical metastasis models. Mechanistically, TFP caused G0/G1 cell cycle arrest and mitochondrial-dependent intrinsic apoptosis of melanoma cells. In addition, TFP treatment increased the expression of microtubule associated protein 1 light chain 3 beta-II (LC3B-II) and p62 in vitro, suggesting an inhibition of autophagic flux. TFP decreased LysoTracker Red uptake after treatment, indicating impaired acidification of lysosomes. Moreover, the colocalization of LC3 with lysosomal-associated membrane protein 1 (LAMP1), a lysosome marker, was also suppressed after TFP treatment, suggesting that TFP might block the fusion of autophagosomes with lysosomes, which led to autophagosome accumulation. Taken together, our data highlight the potential of repurposing TFP as a new adjuvant drug for treating melanoma patients with brain, lung, and bone metastases.
- Published
- 2021
26. Identification of a potent and selective phosphatidylinositol 3-kinase δ inhibitor for the treatment of non-Hodgkin's lymphoma
- Author
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Wei-Qiong Zuo, Rong Hu, Ning-Yu Wang, Yongxia Zhu, Luoting Yu, Zhihao Liu, Wan-Li Wang, and Ying Xu
- Subjects
MAPK/ERK pathway ,Morpholines ,Antineoplastic Agents ,Mice, SCID ,01 natural sciences ,Biochemistry ,Piperazines ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Phosphatidylinositol ,Enzyme Inhibitors ,Phosphorylation ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Mitogen-Activated Protein Kinase Kinases ,010405 organic chemistry ,Kinase ,Lymphoma, Non-Hodgkin ,Organic Chemistry ,Neoplasms, Experimental ,medicine.disease ,0104 chemical sciences ,Lymphoma ,Non-Hodgkin's lymphoma ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,Purines ,Apoptosis ,Drug Design ,Toxicity ,Cancer research ,Heterografts - Abstract
PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation.
- Published
- 2020
27. A novel small-molecule YLT256 inhibits proliferation and induces apoptosis both in vitro and in vivo in solid tumors
- Author
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Xuejiao Song, Tinghong Ye, Yongxia Zhu, Weiqiong Zuo, Yong Xia, Jun Zeng, Luoting Yu, Hongxia Deng, Ningyu Wang, Lidan Zhang, Yao-Jie Shi, and Tiantao Gao
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Biology ,Models, Biological ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Neoplasms ,Pancreatic cancer ,Thiadiazoles ,medicine ,Animals ,Humans ,Cell Shape ,Cell Proliferation ,Membrane Potential, Mitochondrial ,Pharmacology ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Reactive oxygen species ,TUNEL assay ,Cell growth ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,Clone Cells ,Neoplasm Proteins ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Benzamides ,Cancer research ,Female ,Growth inhibition ,Reactive Oxygen Species - Abstract
Pancreatic carcinoma is a still unsolved health problem all over the world with poor prognosis and high mortality rate. YLT256, a novel synthesized chemical small inhibitor, displays potent antineoplastic activities via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT256 showed growth inhibition against a broad spectrum of human cancer cell lines and pancreatic cancer cell line BxPc-3 was the most sensitive with an IC50 of 0.42μM. We also found YLT256 could induce apoptosis of BxPc-3 cells in a dose-dependent manner. Western blot analysis revealed that the occurrence of its apoptosis was associated with activation of caspases-3 and -9, up-regulation of pro-apoptotic Bak, and down-regulation of anti-apoptotic Bcl-2. Moreover, YLT256-treated resulted in changes of mitochondrial membrane potential (Δψm), and generation of reactive oxygen species (ROS). Furthermore, our data also revealed that YLT256 suppressed the growth of established tumor-bearing xenograft models without obvious side effects. Immunohistochemical analyses and TUNEL assay revealed an increase in cleaved caspase-3-positive cells and TUNEL-positive cells, a decrease in Ki67-positive cells upon YLT256. Together, all the results of present study provided evidence demonstrating that YLT256 could be a promising potential drug candidate for pancreatic cancer therapy.
- Published
- 2016
28. ZLD1122, a novel EZH2 and EZH1 small molecular inhibitor, blocks H3K27 methylation and diffuse large B cell lymphoma cell growth
- Author
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Xuejiao Song, Ningyu Wang, Cui-Ting Peng, Tiantao Gao, Lidan Zhang, Luoting Yu, Weiqiong Zuo, Li Liu, Menghua Xiong, Qiang Feng, Hongxia Deng, Suxia Shi, Yong Xia, Yongxia Zhu, Qian Lei, Xin-Yu You, and Tinghong Ye
- Subjects
0301 basic medicine ,biology ,Chemistry ,Cell growth ,General Chemical Engineering ,EZH2 ,Wild type ,macromolecular substances ,General Chemistry ,medicine.disease ,Molecular biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Histone methyltransferase ,medicine ,biology.protein ,H3K4me3 ,PRC2 ,Diffuse large B-cell lymphoma - Abstract
The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been reported to be overexpressed in a variety of cancers and is associated with tumor malignancy. This is mainly because EZH2 catalyzes the hypertrimethylation of histone 3 at lysine 27 (H3K27) at the promoter of target genes, leading to the silencing of downstream tumor suppressor genes. Hence, blocking its catalytic function may be a therapeutic strategy for the treatment of tumors which over-express or have a gain-of-function mutation in EZH2, such as lymphomas. Here, we reported a novel, selective, small-molecule inhibitor of EZH2 and EZH1 synthesized by us, ZLD1122, which inhibited both EZH1 and wild type and mutant EZH2 activities with nanomolar potency. ZLD1122 significantly inhibited intracellular H3K27 trimethylation without affecting the levels of H3, H3K9me3, and H3K4me3, indicating its selective inhibition of polycomb repressive complex 2 (PRC2) methyl catalytic function. Moreover, ZLD1122 induced G0/G1 phase arrest in diffuse large B cell lymphoma (DLBCL) cells in a dose-dependent manner via downregulation of cyclinE and CDK4 as well as upregulation of p21 and cyclinD1. Furthermore, it induced apoptosis and loss of mitochondrial membrane potential (Δψm), and elevated the levels of cleaved caspase-9 in Su-DHL-6 and Pfeiffer cells, suggesting that ZLD1122 suppresses the viability of DLBCL cells by inducing caspase-mediated intrinsic apoptosis. Taken together, these data demonstrated that ZLD1122, owing to its pharmacologically inhibitory activity against EZH2, could be a promising agent for the treatment of lymphomas with EZH2 gain-of-function mutations.
- Published
- 2016
29. Penfluridol: An antipsychotic agent suppresses lung cancer cell growth and metastasis by inducing G0/G1 arrest and apoptosis
- Author
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Fanfan Jia, Qianqian Wang, Weiqiong Zuo, Jun Zeng, Zhanzhan Feng, Luoting Yu, Yong Xia, Zhihao Liu, Yongxia Zhu, Ying Xu, Xi Hu, Tiantao Gao, and Qiang Xue
- Subjects
0301 basic medicine ,Lung Neoplasms ,Cell cycle checkpoint ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,RM1-950 ,Resting Phase, Cell Cycle ,Penfluridol ,Metastasis ,Cell cycle arrest ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Lung cancer ,Pharmacology ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,business.industry ,Intrinsic apoptosis ,G1 Phase ,Cell Cycle Checkpoints ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,Growth Inhibitors ,030104 developmental biology ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Therapeutics. Pharmacology ,business ,Antipsychotic Agents ,medicine.drug - Abstract
Lung cancer remains the leading cause of cancer mortality because of highly malignant and metastatic potential. The current status of lung cancer treatment is limited, and more treatment options are needed. Interesting, antipsychotic drugs have been reported to show anti-cancer effects. In this present study, we investigated the anticancer potential of penfluridol (PF), an anti-schizophrenic drug, in lung cancer and its underlying mechanism in vitro and in vivo. In vitro, it could inhibit the viability of various lung cancer cells with G0/G1 phase arrest via increasing the expression level of p21/p27 and decreasing the expression levels of cyclin-CDK complex. Meanwhile, cell-cycle arrest causes DNA repair in the nucleus, which was associated with the upregulation of H2A.X and p-H2A.X. Moreover, PF could also decrease mitochondrial membrane potential and increase reactive oxygen species levels in the lung cancer cells. These results implied that PF might induce the mitochondria-mediated intrinsic apoptosis. In addition, PF inhibits the migration and invasion of lung cancer cells via downregulation of FAK-MMP signaling. In vivo, oral administration of PF at concentration of 10 mg/kg inhibited tumor growth in A549 xenograft model. Notably, PF is an approved drug and the price is exceedingly cheap, so this study demonstrates the potential of PF to treat lung cancer.
- Published
- 2020
30. The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis
- Author
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Zhilin Zeng, Cui-Ting Peng, Yong Xia, Zhiqiang Ran, Ranran Wang, Luoting Yu, Yufei Yang, Qianqian Wang, Xi Hu, Qian Lei, Qiang Xue, Tiantao Gao, Zhanzhan Feng, Zixin Xie, Nan Yang, and Fuyan Xu
- Subjects
0301 basic medicine ,Cancer Research ,Immunology ,Mice, Nude ,Apoptosis ,Triple Negative Breast Neoplasms ,Mice, SCID ,Trifluoperazine ,Resting Phase, Cell Cycle ,Article ,Trifluoperazine Hydrochloride ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Breast cancer ,Mice, Inbred NOD ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:QH573-671 ,Triple-negative breast cancer ,Cell Proliferation ,Mice, Inbred BALB C ,Brain Neoplasms ,Caspase 3 ,lcsh:Cytology ,business.industry ,G1 Phase ,Brain ,Cell Cycle Checkpoints ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,Mitochondria ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Female ,business ,Antipsychotic Agents ,medicine.drug ,Brain metastasis - Abstract
Women with aggressive triple-negative breast cancer (TNBC) are at high risk of brain metastasis, which has no effective therapeutic option partially due to the poor penetration of drugs across the blood−brain barrier. Trifluoperazine (TFP) is an approved antipsychotic drug with good bioavailability in brain and had shown anticancer effect in several types of cancer. It drives us to investigate its activities to suppress TNBC, especially the brain metastasis. In this study, we chose three TNBC cell lines MDA-MB-468, MDA-MB-231, and 4T1 to assess its anticancer activities along with the possible mechanisms. In vitro, it induced G0/G1 cell cycle arrest via decreasing the expression of both cyclinD1/CDK4 and cyclinE/CDK2, and stimulated mitochondria-mediated apoptosis. In vivo, TFP suppressed the growth of subcutaneous xenograft tumor and brain metastasis without causing detectable side effects. Importantly, it prolonged the survival of mice bearing brain metastasis. Immunohistochemical analysis of Ki67 and cleaved caspase-3 indicated TFP could suppress the growth and induce apoptosis of cancer cells in vivo. Taken together, TFP might be a potential available drug for treating TNBC with brain metastasis, which urgently needs novel treatment options.
- Published
- 2018
31. Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer
- Author
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Lu Li, Luoting Yu, Zhihao Liu, Jia Wang, Guoquan Wan, Xi Hu, Qiangsheng Zhang, and Xiuli Wu
- Subjects
Models, Molecular ,Pyridones ,Antineoplastic Agents ,Apoptosis ,01 natural sciences ,Polymerization ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Tubulin ,Microtubule ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Cell Proliferation ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Kinase ,Organic Chemistry ,Cancer ,Neoplasms, Experimental ,General Medicine ,Cell cycle ,medicine.disease ,0104 chemical sciences ,chemistry ,Biochemistry ,Purines ,Cell culture ,Toxicity ,Drug Screening Assays, Antitumor ,Lead compound - Abstract
A new series of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives were designed, synthesized and demonstrated to act as tubulin polymerization inhibitors. These new derivatives showed significant antitumor activities, among which SKLB0533 demonstrated to be the most potent compound, with IC50 values ranging from 44.5 to 135.5 nM against seven colorectal carcinoma (CRC) cell lines. Remarkably, SKLB0533 exhibited no activity against other potential targets, such as 420 kinases and EZH2. Besides, SKLB0533 inhibited tubulin polymerization, arrested the cell cycle at the G2/M phase and induced apoptosis in CRC cells. Furthermore, SKLB0533 suppressed tumour growth in the HCT116 xenograft model without inducing notable major organ-related toxicity, suggesting that SKLB0533 could be used as a promising lead compound for the development of new antitumor agents.
- Published
- 2019
32. Corrigendum to 'Cryptotanshinone induces melanoma cancer cells apoptosis via ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion' [Biomed. Pharmacother. 82 (2016) 319–326]
- Author
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Li Yang, Yiwen Zhang, Luoting Yu, Lifeng Zhao, Tinghong Ye, Yongxia Zhu, Shirui Zhu, Qiang Feng, Bing He, and Yiong Xiong
- Subjects
Pharmacology ,business.industry ,Apoptosis ,Cancer research ,Medicine ,Cell migration ,Therapeutics. Pharmacology ,RM1-950 ,General Medicine ,Melanoma cancer ,business - Published
- 2019
33. Author Correction: Structural and functional studies on Pseudomonas aeruginosa DspI: implications for its role in DSF biosynthesis
- Author
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Li-Hui He, Luoting Yu, Qing-Jie Xiao, Cui-Ting Peng, Tao Li, Tinghong Ye, Rui Bao, Chang-Cheng Li, Yi-Bo Zhu, Li Liu, Ying-Jie Song, Mao Lian, Zhenling Wang, Ning-Yu Wang, Xingjun Cheng, and Si-Min Ju
- Subjects
010302 applied physics ,Multidisciplinary ,Pseudomonas aeruginosa ,lcsh:R ,lcsh:Medicine ,02 engineering and technology ,Computational biology ,Isomerase ,021001 nanoscience & nanotechnology ,medicine.disease_cause ,01 natural sciences ,chemistry.chemical_compound ,Biosynthesis ,chemistry ,0103 physical sciences ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,medicine ,lcsh:Q ,Functional studies ,lcsh:Science ,0210 nano-technology - Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
- Published
- 2018
34. Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity
- Author
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Qiang Feng, Lidan Zhang, Luoting Yu, Zhihao Liu, Tiantao Gao, Yongxia Zhu, Qiangsheng Zhang, Hualong He, and Xin Tao
- Subjects
Lung Neoplasms ,Morpholines ,Cell ,Antineoplastic Agents ,macromolecular substances ,Chemistry Techniques, Synthetic ,010402 general chemistry ,01 natural sciences ,Catalysis ,Metastasis ,Inorganic Chemistry ,Structure-Activity Relationship ,Suzuki reaction ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Drug Discovery ,medicine ,Structure–activity relationship ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Physical and Theoretical Chemistry ,Enzyme Inhibitors ,Lung cancer ,Molecular Biology ,Cell Proliferation ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,EZH2 ,Cancer ,General Medicine ,medicine.disease ,0104 chemical sciences ,medicine.anatomical_structure ,Biochemistry ,Cell culture ,Drug Screening Assays, Antitumor ,Information Systems - Abstract
The histone lysine methyltransferase EZH2 has been reported to play important roles in cancer aggressiveness, metastasis and poor prognosis. In this study, a series of benzomorpholine derivatives were synthesized and biologically evaluated as EZH2 inhibitors. The target compounds were obtained in good yields from 3-amino-5-bromo-2-hydroxybenzoic acid via cyclization, Suzuki coupling and amidation as the key steps. A preliminary optimization study led to the discovery of several potent novel EZH2 inhibitors (6b, 6c, 6x and 6y). Moreover, 6y inhibited the A549 and NCI-H1975 cell lines (IC50 = 1.1 µM and 1.1 µM, respectively). Further studies indicated that 6y can reduce EZH2 expression in intact cells and cause cell arrest in the G2/M phase.
- Published
- 2018
35. Identification of a new series of benzothiazinone derivatives with excellent antitubercular activity and improved pharmacokinetic profiles
- Author
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Luoting Yu, Chao Gao, Yuquan Wei, Kun-Lin Liu, Ning-Yu Wang, Yiwen Zhang, Juan Rong, Qian Lei, Lu Xiong, Tao Xin, Yao-Jie Shi, and Cui-Ting Peng
- Subjects
0301 basic medicine ,biology ,Chemistry ,medicine.drug_class ,General Chemical Engineering ,General Chemistry ,Antimycobacterial ,biology.organism_classification ,01 natural sciences ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,Mycobacterium tuberculosis ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,030104 developmental biology ,Pharmacokinetics ,In vivo ,medicine ,Moiety ,Cytotoxicity ,ADME - Abstract
Nitrobenzothiazinone (BTZ) is a promising scaffold with potent activity against M. tuberculosis by inhibiting decaprenylphosphoryl-beta-D-ribose 2′-oxidase (DprE1). But unfavorable durability poses a challenge to further development of this class of agents. Herein, a series of BTZs bearing a variety of different substituents at the C-2 position were designed and synthesized. Compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Ra and were profiled for metabolic stability, plasma protein-binding capacity and pharmacokinetics in vivo. In general, these new BTZs containing N-piperazine, N-piperidine or N-piperidone moiety have excellent antitubercular activity and low cytotoxicity. Several of the compounds showed improved microsomal stability and lower plasma protein-binding, opening a new direction for further lead optimization. And we obtained compound 3o, which maintained good anti-tuberculosis activity (MIC = 8 nM) and presented better in vitro ADME/T and in vivo pharmacokinetic profiles than reported BTZ compound PBTZ169, which may serve as a candidate for the treatment of tuberculosis.
- Published
- 2018
36. Synthesis and antitubercular evaluation of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives
- Author
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Cui-Ting Peng, Ying Xv, Chao Gao, Hongxia Deng, Luoting Yu, Xin-Yu You, Ningyu Wang, Kai Ran, Qian Lei, Weiqiong Zuo, Kun-Jie Xiao, Yongxia Zhu, and Lidan Zhang
- Subjects
Tuberculosis ,Clinical Biochemistry ,Antitubercular Agents ,Thiazines ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Biochemistry ,Piperazines ,Mycobacterium tuberculosis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Chlorocebus aethiops ,Drug Discovery ,Aqueous solubility ,medicine ,Side chain ,Animals ,Organic chemistry ,Cytotoxicity ,Piperazine ,Vero Cells ,Molecular Biology ,Alkyl ,chemistry.chemical_classification ,Aqueous solution ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,medicine.disease ,biology.organism_classification ,Combinatorial chemistry ,Molecular Medicine - Abstract
Tuberculosis (TB) remains a major human health problem. New therapeutic antitubercular agents are urgent needed to control the global tuberculosis pandemic. We synthesized a new series of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives and evaluated their anti-mycobacterial activities against Mycobacterium tuberculosis H37Ra as well as their druggabilities. The results showed that most of these derivatives, especially the compounds with simple alkyl side chains, exhibited good antitubercular activities and favorable aqueous solubilities with no obvious cytotoxicity. It suggested that the 4-carbonyl piperazine substituents in benzothiazinone scaffold were well tolerated, in which the compound 8h, with an antitubercular activity of MIC 0.008 μM, exhibited an excellent aqueous solubility of 104 μg/mL, which was 100-fold better than the potent DprE1 inhibitor Comp.1 (BTZ038), also more soluble than PBTZ169.
- Published
- 2015
37. Design, synthesis and biological evaluation of novel 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors
- Author
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Xin-Yu You, Xuejiao Song, Chao Gao, Lifeng Zhao, Ying Xu, Yong Luo, Qiyi Zhang, Luoting Yu, Bing He, Cui-Ting Peng, Tiantao Gao, Menghua Xiong, Qiang Feng, Ningyu Wang, and Lidan Zhang
- Subjects
Poor prognosis ,Chemistry ,General Chemical Engineering ,EZH2 ,Cell ,Cancer ,macromolecular substances ,General Chemistry ,medicine.disease ,Metastasis ,medicine.anatomical_structure ,Design synthesis ,Biochemistry ,medicine ,Potency ,Biological evaluation - Abstract
The histone lysine methyltransferase EZH2 has been implicated as a key component in cancer aggressiveness, metastasis and poor prognosis. This study discovered a new class of hexahydroisoquinolin derivatives as EZH2 inhibitors. A structure–activity relationship study showed that the steric hindrance was important to the activity for EZH2. A preliminary optimization study led to the discovery of several potent compounds with low nanomolar to sub-nanomolar potency for EZH2. Biological evaluation indicated that SKLB1049 was a highly potent with improved solubility compared to EPZ6438, SAM-competitive, and cell-active EZH2 inhibitor that decreased global H3K27me3 in SU-DHL-6 and Pfeiffer lymphoma cells in a concentration- and time-dependent manner. Further study indicated that SKLB1049 caused cell arrest in G0/G1 phase. These compounds would be useful as chemical tools to further explore the biology of EZH2 and provided us with a start point to develop new EZH2 inhibitors.
- Published
- 2015
38. A novel benzothiazole derivative SKLB826 inhibits human hepatocellular carcinoma growth via inducing G2/M phase arrest and apoptosis
- Author
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Xuejiao Song, Tinghong Ye, Lidan Zhang, Ying Xu, Yongxia Zhu, Qian Lei, Yong Xia, Ningyu Wang, Luoting Yu, Xiaowei Liu, and Fangfang Yang
- Subjects
Cyclin-dependent kinase 1 ,Chemistry ,Stereochemistry ,General Chemical Engineering ,Cancer ,General Chemistry ,medicine.disease ,chemistry.chemical_compound ,Benzothiazole ,Apoptosis ,Cell culture ,Hepatocellular carcinoma ,Toxicity ,Cancer research ,medicine ,Growth inhibition - Abstract
Hepatocellular carcinoma is the fifth most common cancer and durable responses in conventional treatments are limited so researchers have been devoted to developing new anti-HCC agents. Benzothiazole derivatives are known for various biological activities and have received considerable attention in cancer therapy, hence we designed and synthesized a novel potent benzothiazole compound 2-chloro-N-(2-(2-(2-morpholino-2-oxoethyl)thio)-2,3-dihydrobenzo[d]thiazol-6-yl)acetamide (SKLB826) and further investigated the biological activities against cancer. The results suggested that SKLB826 showed growth inhibition against a broad spectrum of human cancer cells, especially human HCC cell lines, in a dose-dependent manner and induced G2/M phase arrest via down-regulating the CDK1, cyclinA2 and cdc25c protein levels. SKLB826 could also induce apoptosis of HCC cells via decreasing the expression of Bcl-2 and increasing the levels of BAX and cleaved caspase-3, 9. Moreover, after treatment with SKLB826, the change of ROS level and ΔΨm suggested that SKLB826 might induce apoptosis through an intrinsic mitochondrial apoptotic pathway. Furthermore, SKLB826 could suppress tumor growth in the HepG2 xenograft model without inducing any notable major organ-related toxicity, suggesting that SKLB826 may be a potential candidate for HCC therapy.
- Published
- 2015
39. Mannosylated liposomes improve therapeutic effects of paclitaxel in colon cancer models
- Author
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Yong Xia, Ningyu Wang, Qian Lei, Menghua Xiong, Luoting Yu, Xin-Yu You, Tinghong Ye, Lidan Zhang, Tiantao Gao, and Xuejiao Song
- Subjects
Paclitaxel ,Colorectal cancer ,medicine.medical_treatment ,Pharmaceutical Science ,Bioengineering ,Receptors, Cell Surface ,02 engineering and technology ,Pharmacology ,Targeted therapy ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Colloid and Surface Chemistry ,Drug Delivery Systems ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Lectins, C-Type ,Physical and Theoretical Chemistry ,Cytotoxicity ,Liposome ,Mice, Inbred BALB C ,Chemistry ,Organic Chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,Antineoplastic Agents, Phytogenic ,carbohydrates (lipids) ,Mannose-Binding Lectins ,Targeted drug delivery ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Liposomes ,Female ,0210 nano-technology ,Mannose ,Mannose receptor ,Mannose Receptor - Abstract
Mannose receptor (MR) is a highly effective endocytic receptor. It is closely related to tumour immune escape and metastasis. We found that MR was highly expressed in some colon cancer cell lines such as CT26 and HCT116 cells. Therefore, MR might be a potential target in colon cancer therapy. In this study, we aimed to develop mannosylated liposomes containing anticancer drug paclitaxel and investigate the potential effects on targeted therapy for colon cancer. Mannosylated liposomes were prepared by film dispersion method. Characterisation, drug release behaviour, cytotoxicity, cellular uptake, anti-tumour efficacy and safety profiles of liposomes were investigated. The results showed that mannosylated liposomes had a higher CT26 cells uptake efficiency and tumour inhibition rate, which might be due to the target effect to MR. And no notable toxicity was observed. Taken together, these data demonstrated that mannosylated liposomes could target colon cancer and improve the efficacy of chemotherapy.
- Published
- 2017
40. A Novel Small-Molecule YLT205 Induces Apoptosis in Human Colorectal Cells via Mitochondrial Apoptosis Pathway In Vitro and Inhibits Tumor Growth In Vivo
- Author
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Luoting Yu, Yuanping Han, Ningyu Wang, Yong Luo, Xuan-Hong Shi, Tinghong Ye, Yongxia Zhu, Li Liu, Xuejiao Song, Yong Xia, and Jun Zeng
- Subjects
Physiology ,Colorectal cancer ,Cell Survival ,Transplantation, Heterologous ,Down-Regulation ,Mice, Nude ,Apoptosis ,Mouse model of colorectal and intestinal cancer ,Biology ,lcsh:Physiology ,Amino Acid Chloromethyl Ketones ,lcsh:Biochemistry ,Mice ,In vivo ,Cell Line, Tumor ,Acetamides ,medicine ,Animals ,Humans ,MTT assay ,lcsh:QD415-436 ,Benzothiazoles ,Phosphorylation ,Protein kinase A ,Protein kinase B ,bcl-2-Associated X Protein ,Flavonoids ,Membrane Potential, Mitochondrial ,lcsh:QP1-981 ,Cytochrome c ,Cytochromes c ,Mitochondrial pathway ,medicine.disease ,HCT116 Cells ,Molecular biology ,Mitochondria ,YLT205 ,biology.protein ,Human colorectal cancer ,Colorectal Neoplasms - Abstract
Background: Colorectal cancer continues to be one of the most common causes of cancer death, and the poor survival rates and liver metastases at the time of diagnosis urgently need more effective strategy for colorectal cancer treatment. Methods: The activities of N-(5-bromopyridin-2-yl)-2-((6-(2-chloroacetamido)benzo[d]thiazol-2-yl)thio)acetamide (YLT205), which is a novel small molecule compound synthesized by us, were investigated using MTT assay, flow cytometry, western blotting and mice tumor xenograft models. Results: YLT205 induced apoptosis of human colorectal cell lines in a dose-dependent manner. The occurrence of apoptosis was associated with activation of caspases-9 and -3, down-regulation of Bcl-2 and up-regulation of Bax in HCT116 cells. Moreover, YLT205 disrupted mitochondrial membranes and induced the release of cytochrome c into cytosol. Impaired phosphorylation of p44/42 mitogen-activated protein kinase was also observed while the expression of phosphorylated protein kinase B (Akt) was not affected. Furthermore, in HCT116 and SW620 tumor-bearing nude mice models, YLT205 dose-dependently inhibited tumor growth without obvious adverse effects. Immunohistochemistry analyses revealed YLT205 also induced apoptosis and inhibited tumor cell proliferation in vivo. Conclusion: These studies suggested that YLT205 might be a potential drug candidate for human colorectal cancer therapy.
- Published
- 2014
41. Reductions in Myeloid-Derived Suppressor Cells and Lung Metastases using AZD4547 Treatment of a Metastatic Murine Breast Tumor Model
- Author
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Ting Hong Ye, Hang Song, Yong Kui Zhang, Ningyu Wang, Yuan Ping Han, De Liang Li, Ying Xiong, Luoting Yu, Yong Xia Zhu, Li Liu, Yong Xia, Yu Quan Wei, Xue Jiao Song, Kai Ran, Jun Zeng, and Cui Ting Peng
- Subjects
CD4-Positive T-Lymphocytes ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Physiology ,T cells ,MDSCs ,Tumor M2-PK ,CD8-Positive T-Lymphocytes ,Piperazines ,lcsh:Physiology ,Metastasis ,lcsh:Biochemistry ,Mice ,Breast cancer ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Myeloid Cells ,lcsh:QD415-436 ,Neoplasm Metastasis ,Tumor microenvironment ,lcsh:QP1-981 ,business.industry ,Mammary Neoplasms, Experimental ,medicine.disease ,FGFR inhibitor ,Fibroblast growth factor receptor ,Apoptosis ,Benzamides ,AZD4547 ,Myeloid-derived Suppressor Cell ,Pyrazoles ,Female ,Drug Screening Assays, Antitumor ,business ,Tyrosine kinase - Abstract
d These authors contributed equally to this work Abstract Background: AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs), is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment. Methods: First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs) in lung, spleens, peripheral blood and tumor. Results: Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4 + and CD8 + T-cells were significantly increased in tumor and spleens. Conclusion: Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.
- Published
- 2014
42. Development of Intravenous Formulation of a Novel Multikinase Inhibitor for Treating Cancer Based on 2-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
- Author
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Hongjun Lin, Luoting Yu, Xun Luo, Shengyong Yang, Jun He, Yongmei Xie, Shuangzhi Li, Xiangrong Song, Yinglan Zhao, Junming Li, and Ningyu Wang
- Subjects
Health (social science) ,General Computer Science ,Chemistry ,General Mathematics ,General Engineering ,Cancer ,Pharmacology ,medicine.disease ,Education ,Multikinase inhibitor ,General Energy ,2 hydroxypropyl β cyclodextrin ,medicine ,General Environmental Science - Published
- 2012
43. Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis
- Author
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Ningyu Wang, Kun Liu, Lidan Zhang, Chao Gao, Luoting Yu, Yuquan Wei, Kai Ran, Weiqiong Zuo, Cui-Ting Peng, Yongxia Zhu, Xin-Yu You, Tinghong Ye, Lu Xiong, and Yao-Jie Shi
- Subjects
0301 basic medicine ,Tuberculosis ,030106 microbiology ,Antitubercular Agents ,Drug Evaluation, Preclinical ,Drug resistance ,Pharmacology ,Article ,Mycobacterium tuberculosis ,03 medical and health sciences ,Bacterial Proteins ,In vivo ,Tuberculosis, Multidrug-Resistant ,medicine ,Humans ,Enzyme Inhibitors ,Multidisciplinary ,biology ,business.industry ,Drug resistant tuberculosis ,biology.organism_classification ,medicine.disease ,Bioavailability ,Alcohol Oxidoreductases ,030104 developmental biology ,Antagonism ,business ,Rifampicin ,medicine.drug - Abstract
New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis.
- Published
- 2016
44. Corrigendum: Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer
- Author
-
Xuejiao Song, Qiang Feng, Fangfang Yang, Lidan Zhang, Yongxia Zhu, Tiantao Gao, Luoting Yu, Qian Lei, Yao-Jie Shi, Xin-Yu You, Yuquan Wei, Ningyu Wang, Yong Xia, Tinghong Ye, and Menghua Xiong
- Subjects
0301 basic medicine ,Antitumor activity ,Multidisciplinary ,business.industry ,EZH2 ,Selective inhibition ,medicine.disease ,Corrigenda ,03 medical and health sciences ,030104 developmental biology ,Breast cancer ,Cell culture ,Ic50 values ,medicine ,Cancer research ,Breast cancer cells ,business - Abstract
Scientific Reports 6: Article number: 20864; Published online: 12 February 2016; Updated: 29 April 2016 This Article contains typographical errors. In the Results section under subheading ‘Impact of ZLD1039 on breast cancer cell growth’, “Among the cell lines, MCF-7 and ZR-75-1 were the most sensitive to ZLD1039 with IC50 values of 0.
- Published
- 2016
45. Cryptotanshinone induces melanoma cancer cells apoptosis via ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion
- Author
-
Tinghong Ye, Yongxia Zhu, Yiwen Zhang, Yiong Xiong, Luoting Yu, Lifeng Zhao, Bing He, Li Yang, Shirui Zhu, and Qiang Feng
- Subjects
0301 basic medicine ,Skin Neoplasms ,Cell Survival ,Apoptosis ,Biology ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Cell Shape ,Melanoma ,Tumor Stem Cell Assay ,Cell Proliferation ,Pharmacology ,medicine.diagnostic_test ,Cell growth ,Cell migration ,General Medicine ,Cell cycle ,Phenanthrenes ,medicine.disease ,Cell biology ,Mitochondria ,G2 Phase Cell Cycle Checkpoints ,030104 developmental biology ,030220 oncology & carcinogenesis ,Signal transduction ,Reactive Oxygen Species ,Signal Transduction - Abstract
Melanoma is the most serious type of skin cancer because it is highly frequency of drug resistance and can spread earlier and more quickly than other skin cancers. The objective of this research was to investigate the anticancer effects of cryptotanshinone on human melanoma cells in vitro, and explored its mechanisms of action. Our results have shown that cryptotanshinone could inhibit cell proliferation in human melanoma cell lines A2058, A375, and A875 in a dose- and time-dependent manner. In addition, flow cytometry assay showed that cryptotanshinone inhibited the proliferation of human melanoma cell line A375 by blocking cell cycle progression in G2/M phase and inducing apoptosis in a concentration-dependent manner. Moreover, western blot analysis indicated that the occurrence of its apoptosis was associated with upregulation of cleaved caspases-3 and pro-apoptotic protein Bax while downregulation of anti-apoptotic protein Bcl-2. Meanwhile, cryptotanshinone could decrease the levels of reactive oxygen species (ROS). Furthermore, cryptotanshinone also blocked A375 cell migration and invasion in vitro which was associated with the downregulation with MMP-9. Taken together, these results suggested that cryptotanshinone might be a potential drug in human melanoma treatment by inhibiting proliferation, inducing apoptosis via ROS-mitochondrial apoptotic pathway and blocking cell migration and invasion.
- Published
- 2016
46. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma
- Author
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Xuejiao Song, Yuquan Wei, Yongxia Zhu, Lifeng Zhao, Ningyu Wang, Hongxia Deng, Xi Yu, Qian Lei, Li Liu, Tinghong Ye, Yongmei Xie, Lidan Zhang, Ying Xiong, Tiantao Gao, Luoting Yu, Weiqiong Zuo, Fangfang Yang, Yong Xia, and Cui-Ting Peng
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cell Survival ,Nitrofurans ,Melanoma, Experimental ,Antineoplastic Agents ,Apoptosis ,Article ,Metastasis ,03 medical and health sciences ,Cell Movement ,Cell Line, Tumor ,Hydroxybenzoates ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,STAT3 ,Melanoma ,Cell Proliferation ,Multidisciplinary ,biology ,business.industry ,Cell growth ,Cell migration ,medicine.disease ,Xenograft Model Antitumor Assays ,Mitochondria ,G2 Phase Cell Cycle Checkpoints ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,biology.protein ,Signal transduction ,business ,Nifuroxazide ,medicine.drug - Abstract
Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma.
- Published
- 2016
47. Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer
- Author
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Xin-Yu You, Qiang Feng, Lidan Zhang, Tinghong Ye, Yongxia Zhu, Yao-Jie Shi, Yuquan Wei, Luoting Yu, Menghua Xiong, Ningyu Wang, Tiantao Gao, Xuejiao Song, Qian Lei, Yong Xia, and Fangfang Yang
- Subjects
0301 basic medicine ,Transcriptional Activation ,Cell cycle checkpoint ,Methyltransferase ,Pyridones ,Intracellular Space ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,macromolecular substances ,Quinolones ,Methylation ,Article ,Metastasis ,Histones ,Small Molecule Libraries ,03 medical and health sciences ,Breast cancer ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Neoplasm Metastasis ,Cell Proliferation ,Mice, Inbred BALB C ,Multidisciplinary ,Cell growth ,business.industry ,EZH2 ,Polycomb Repressive Complex 2 ,Cell Cycle Checkpoints ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Immunology ,Benzamides ,Cancer research ,Female ,business - Abstract
Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer.
- Published
- 2016
48. Identification of novel 2-aminothiazole conjugated nitrofuran as antitubercular and antibacterial agents
- Author
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Yao-Jie Shi, Cui-Ting Peng, Chao Gao, Xin-Yu You, Lu Xiong, Ningyu Wang, Kai Ran, Hongxia Deng, Wei Wei, Qian Lei, Kun-Jie Xiao, Luoting Yu, and Zhihao Liu
- Subjects
0301 basic medicine ,Staphylococcus aureus ,medicine.drug_class ,Nitrofurans ,Clinical Biochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Pharmacology ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Mycobacterium tuberculosis ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Aminothiazole ,Drug Discovery ,Chlorocebus aethiops ,medicine ,Structure–activity relationship ,Animals ,Tuberculosis ,Benzamide ,Cytotoxicity ,Molecular Biology ,Nitrofuran ,Vero Cells ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Antimicrobial ,biology.organism_classification ,0104 chemical sciences ,Anti-Bacterial Agents ,Thiazoles ,030104 developmental biology ,Molecular Medicine - Abstract
The emergence of antibiotic resistant pathogens is an ongoing main problem in the therapy of bacterial infections. In order to develop promising antitubercular and antibacterial lead compounds, we designed and synthesized a new series of derivatives of 2-aminothiazole conjugated nitrofuran with activities against both Mycobacterium tuberculosis and Staphylococcus aureus. Eight compounds 12e, 12k, 12l, 12m, 18a, 18d, 18e, and 18j emerged as promising antitubercular agents. Structure-activity relationships (SARs) were discussed and showed that the derivatives substituted at the position-3 of benzene of 5-nitro-N-(4-phenylthiazol-2-yl)furan-2-carboxamide exhibited superior potency. The most potent compound 18e, substituted with benzamide at this position, displayed minimum inhibitory concentrations (MICs) of 0.27μg/mL against Mtb H37Ra and 1.36μg/mL against S. aureus. Furthermore, compound 18e had no obvious cytotoxicity to normal Vero cells (IC50=50.2μM). The results suggest that the novel scaffolds of aminothiazole conjugated nitrofuran would be a promising class of potent antitubercular and antimicrobial agents.
- Published
- 2016
49. Selective inhibition of EZH2 by ZLD10A blocks H3K27 methylation and kills mutant lymphoma cells proliferation
- Author
-
Luoting Yu, Xuejiao Song, Tiantao Gao, Qian Lei, Qiang Feng, Hongxia Deng, Tinghong Ye, Bing He, Lidan Zhang, and Yongxia Zhu
- Subjects
0301 basic medicine ,Lymphoma ,Mutant ,Apoptosis ,macromolecular substances ,medicine.disease_cause ,Methylation ,Histones ,03 medical and health sciences ,Histone H3 ,Cell Line, Tumor ,medicine ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Cell Shape ,Cell Proliferation ,Pharmacology ,Genetics ,biology ,Cell growth ,Lysine ,EZH2 ,General Medicine ,Cell Cycle Checkpoints ,Histone-Lysine N-Methyltransferase ,medicine.disease ,Isoquinolines ,030104 developmental biology ,Histone methyltransferase ,Benzamides ,Mutation ,biology.protein ,Cancer research ,Histone Methyltransferases ,PRC2 ,Carcinogenesis ,Diffuse large B-cell lymphoma - Abstract
EZH2 (Enhancer of zeste homolog 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is involved in repressing gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation. EZH2 overexpression is implicated in tumorigenesis and has been a candidate oncogene in several tumor types. Recently, point mutations of EZH2 at Tyr641 and Ala677 were identified in diffuse large B cell lymphoma and follicular lymphoma, where they drive H3K27 hypertrimethylation and cancer progression. Here, we reported a novel, highly potent and selective small molecule inhibitor of EZH2, ZLD10A, which inhibited wild-type and mutant versions of EZH2 with nanomolar potency and had greater than 1000-fold selectivity against 10 other histone methyltransferases. Our results have shown that the compound suppressed global H3K27 methylation and cause the anti-proliferation effects in a concentration- and time-dependent manner in DLBCL cell lines. These results demonstrated that ZLD10A, as a novel EZH2 inhibitor, could be a potential promising agent for the treatment of EZH2 mutant lymphoma.
- Published
- 2015
50. Novel Pyrazolo[3,4-d]pyrimidine Derivatives as Potential Antitumor Agents: Exploratory Synthesis, Preliminary Structure-Activity Relationships, and in Vitro Biological Evaluation
- Author
-
Luoting Yu, Shengyong Yang, Jin-Ni Zhao, Li Yang, Ruo Jia, Hai-Yun He, and Yinglan Zhao
- Subjects
Pyrimidine ,Stereochemistry ,Cell ,Pharmaceutical Science ,Antineoplastic Agents ,exploratory synthesis ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Structure-Activity Relationship ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Cell Line, Tumor ,pyrazolo[3,4-d]pyrimidine ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,Doxorubicin ,Physical and Theoretical Chemistry ,anticancer activity ,apoptosis ,Cell Proliferation ,A549 cell ,Chemistry ,Cell growth ,Organic Chemistry ,In vitro ,Pyrimidines ,medicine.anatomical_structure ,Biochemistry ,Chemistry (miscellaneous) ,Cell culture ,Pyrazoles ,Molecular Medicine ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC₅₀ for A549 cells was 2.24 µM, compared with an IC₅₀ of 9.20 µM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies.
- Published
- 2011
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