11 results on '"Qi-Zheng Sun"'
Search Results
2. Progress of small molecular inhibitors in the development of anti-influenza virus agents
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Qi-Zheng Sun, Chun-Hui Zhang, Lin Li, Shengyong Yang, Xiao-Ai Wu, Zhiyun Jia, and Xiuli Wu
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M2 ion channel protein inhibitors ,0301 basic medicine ,anti-influenza virus agent ,Medicine (miscellaneous) ,Hemagglutinin (influenza) ,Review ,medicine.disease_cause ,Antiviral Agents ,RNA-dependent RNA polymerase inhibitors ,neuraminidase inhibitors ,Virus ,03 medical and health sciences ,Human health ,Drug Discovery ,Pandemic ,Animals ,Humans ,Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Influenza treatment ,biology ,business.industry ,hemagglutinin inhibitors ,virus diseases ,Influenza pandemic ,Orthomyxoviridae ,Virology ,Influenza A virus subtype H5N1 ,030104 developmental biology ,biology.protein ,business ,Neuraminidase - Abstract
The influenza pandemic is a major threat to human health, and highly aggressive strains such as H1N1, H5N1 and H7N9 have emphasized the need for therapeutic strategies to combat these pathogens. Influenza anti-viral agents, especially active small molecular inhibitors play important roles in controlling pandemics while vaccines are developed. Currently, only a few drugs, which function as influenza neuraminidase (NA) inhibitors and M2 ion channel protein inhibitors, are approved in clinical. However, the acquired resistance against current anti-influenza drugs and the emerging mutations of influenza virus itself remain the major challenging unmet medical needs for influenza treatment. It is highly desirable to identify novel anti-influenza agents. This paper reviews the progress of small molecular inhibitors act as antiviral agents, which include hemagglutinin (HA) inhibitors, RNA-dependent RNA polymerase (RdRp) inhibitors, NA inhibitors and M2 ion channel protein inhibitors etc. Moreover, we also summarize new, recently reported potential targets and discuss strategies for the development of new anti-influenza virus drugs.
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- 2017
3. Identification of a small molecule that downregulates MITF expression and mediates antimelanoma activity in vitro
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Zhi-Xing Cao, Shengyong Yang, Wei-Wei Li, Qi-Zheng Sun, Shao-Hua Yao, Jin-Feng Shang, Hui-Wen Yang, Xin Chen, and Chuan Cheng
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Melanoma, Experimental ,Down-Regulation ,Antineoplastic Agents ,Dermatology ,Melanocyte ,Small Molecule Libraries ,Melanin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Melanoma ,Zebrafish ,Microphthalmia-Associated Transcription Factor ,biology ,business.industry ,Neural crest ,Cell migration ,medicine.disease ,Microphthalmia-associated transcription factor ,biology.organism_classification ,Embryonic stem cell ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,business - Abstract
Melanoma is a type of cancer arising from the melanocytes, which are the cells that make up the pigment melanin and are derived from the neural crest. There is no particularly effective therapy once the disease is metastatic, highlighting the need for discovery of novel potent agents. In this investigation, we adopted a zebrafish embryonic pigmentation model to identify antimelanoma agents by screening an in-house small molecule library. With this assay, we found that a small molecule compound, SKLB226, blocked zebrafish pigmentation and pigment cell migration. Mechanism of action studies showed that SKLB226 downregulated MITF mRNA level in both zebrafish embryos and mammalian melanoma cells. Further studies showed that it could efficiently suppress the viability and migration of mammalian melanoma cells. In summary, SKLB226 can be used as a chemical tool to study melanocyte development as well as an antimelanoma lead compound that should be subjected to further structural optimization.
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- 2016
4. Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers
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Guangwen Lu, Yuquan Wei, Chong Chen, Rong Xiang, Shengyong Yang, Wei Yang, Guifeng Lin, Kai Chen, Guo Zhang, Qi-Zheng Sun, Lin-Li Li, Luyi Huang, and Xi-Ting Jin
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0301 basic medicine ,Male ,Models, Molecular ,Pharmacology ,Protein Serine-Threonine Kinases ,Protective Agents ,Cell Line ,CLK1 ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Autophagy ,Structure–activity relationship ,Animals ,Humans ,IC50 ,Acetaminophen ,Cyclin-dependent kinase 1 ,Kinase ,Quinoline ,In vitro toxicology ,Stereoisomerism ,Protein-Tyrosine Kinases ,Triazoles ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Liver ,Quinolines ,Molecular Medicine ,Chemical and Drug Induced Liver Injury - Abstract
Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of...
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- 2017
5. Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure-Activity Relationship Analysis
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Yanlin Wang, Guo Zhang, Rong Xiang, Xiang Wang, Qi-Zheng Sun, Shengyong Yang, Shenzhen Huang, Lin-Li Li, Luyi Huang, Chun-Li Song, Yiguo Hu, and Xiaojuan Jiang
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0301 basic medicine ,Cell Survival ,Protein Conformation ,General Chemical Engineering ,Thio ,Library and Information Sciences ,Biology ,Nicotinamide adenine dinucleotide ,SIRT2 ,Molecular Docking Simulation ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Sirtuin 2 ,Structure–activity relationship ,Humans ,Acetylation ,General Chemistry ,Small molecule ,Computer Science Applications ,Histone Deacetylase Inhibitors ,Isoenzymes ,030104 developmental biology ,Biochemistry ,chemistry ,Docking (molecular) ,Drug Design ,MCF-7 Cells ,NAD+ kinase - Abstract
SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure–activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide (SR86). This compound showed good activity against SIRT2 with an IC50 value of 1.3 μM. SR86 did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, SR86 displ...
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- 2017
6. Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor
- Author
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Qi-Zheng Sun, Lin-Li Li, Jing-Jing Liu, Ren-Lin Zheng, Ze-Rong Wang, Yong Xu, Wen-Jing Wang, Chun-Hui Zhang, and Shengyong Yang
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endocrine system ,endocrine system diseases ,Catalysis ,Inorganic Chemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Potency ,Physical and Theoretical Chemistry ,Protein Kinase Inhibitors ,Molecular Biology ,Thyroid cancer ,EGFR inhibitors ,Chemistry ,Kinase ,Cellular Assay ,Proto-Oncogene Proteins c-ret ,Organic Chemistry ,Thyroid cancer cell ,Hep G2 Cells ,General Medicine ,medicine.disease ,Molecular biology ,ErbB Receptors ,Inhibitory potency ,Biochemistry ,Active compound ,Information Systems - Abstract
Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an $$\hbox {IC}_{50}$$ value of 7 nM.
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- 2014
7. Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization
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Heng-Xiu Yan, Jun Zou, Ze-Rong Wang, Shan Feng, Yang Lingling, Pan Ji, Guo-Bo Li, Qi-Zheng Sun, Shuang Ma, and Shengyong Yang
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Models, Molecular ,Pharmacology ,Virtual screening ,Dose-Response Relationship, Drug ,Molecular Structure ,Pyrimidine ,Casein Kinase I ,Stereochemistry ,Organic Chemistry ,General Medicine ,Hit to lead ,Diamines ,Combinatorial chemistry ,High-Throughput Screening Assays ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pyrimidines ,chemistry ,Diamine ,Drug Discovery ,Casein kinase 1 ,Pharmacophore ,Protein Kinase Inhibitors ,Lead compound - Abstract
Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC50 value of 78 nM.
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- 2012
8. Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo
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Shengyong Yang, Shu Zhou, Chan Zou, Xin Chen, Lin-Li Li, Guo-Bo Li, Shan Feng, Li-Jiao Wang, Chuan Cheng, Qi-Zheng Sun, Shuang Ma, and Yang Lingling
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Embryo, Nonmammalian ,Transplantation, Heterologous ,Angiogenesis Inhibitors ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Animals, Genetically Modified ,Mice ,Structure-Activity Relationship ,In vivo ,Cell Line, Tumor ,Drug Discovery ,medicine ,Structure–activity relationship ,Potency ,Animals ,Humans ,Urea ,Zebrafish ,Cell Proliferation ,Chemistry ,Phenylurea Compounds ,Myeloid leukemia ,Vascular Endothelial Growth Factor Receptor-2 ,In vitro ,Transplantation ,Leukemia, Myeloid, Acute ,Pyrimidines ,Mechanism of action ,fms-Like Tyrosine Kinase 3 ,Fms-Like Tyrosine Kinase 3 ,Molecular Medicine ,Pyrazoles ,medicine.symptom ,Drug Screening Assays, Antitumor ,Neoplasm Transplantation ,Signal Transduction - Abstract
We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.
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- 2013
9. Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3- morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo
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Jing-Jing Liu, Li-Jiao Wang, Shengyong Yang, Chun-Hui Zhang, Yong Xu, Yang Lingling, Jiao Yang, Pan Ji, Shan Feng, Zhi-Xing Cao, Ze-Rong Wang, Lei Zhong, Xiaoyan Wang, Yuquan Wei, Ren-Lin Zheng, Heng-Xiu Yan, Shuang Ma, Wei-Wei Li, and Qi-Zheng Sun
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Antineoplastic Agents ,Pharmacology ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Thiadiazoles ,Quinazoline ,medicine ,Structure–activity relationship ,Animals ,Humans ,Thiazole ,Phenylurea Compounds ,Myeloid leukemia ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Leukemia ,Leukemia, Myeloid, Acute ,chemistry ,fms-Like Tyrosine Kinase 3 ,Drug Design ,Quinazolines ,Molecular Medicine ,FLT3 Inhibitor - Abstract
Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.
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- 2012
10. Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers.
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Qi-Zheng Sun, Gui-Feng Lin, Lin-Li Li, Xi-Ting Jin, Lu-Yi Huang, Guo Zhang, Wei Yang, Kai Chen, Rong Xiang, Chong Chen, Yu-Quan Wei, Guang-Wen Lu, and Sheng-Yong Yang
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AUTOPHAGY , *VESICLES (Cytology) , *KINASES , *CRYSTAL structure , *LIVER injuries - Abstract
Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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11. Identification of a small molecule that downregulates MITF expression and mediates antimelanoma activity in vitro.
- Author
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Chuan Cheng, Hui-Wen Yang, Jin-Feng Shang, Wei-Wei Li, Qi-Zheng Sun, Xin Chen, Zhi-Xing Cao, Shao-Hua Yao, and Sheng-Yong Yang
- Published
- 2016
- Full Text
- View/download PDF
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