231 results on '"Jingkang Shen"'
Search Results
2. The discovery of a novel series of potential ERRα inverse agonists based on p-nitrobenzenesulfonamide template for triple-negative breast cancer in vivo
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Zhipei Gao, Tianxiao Wang, Rui Li, Yongli Du, Han Lv, Liudi Zhang, Haifei Chen, Xiaojin Shi, Qunyi Li, and Jingkang Shen
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errα ,tnbc ,p-nitrobenzenesulfonamide ,inverse agonist ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Oestrogen related receptor α participated in the regulation of oxidative metabolism and mitochondrial biogenesis, and was overexpressed in many cancers including triple-negative breast cancer. A set of new ERRα inverse agonists based on p-nitrobenzenesulfonamide template were discovered and compound 11 with high potent activity (IC50 = 0.80 μM) could significantly inhibit the transcription of ERRα-regulated target genes. By regulating the downstream signalling pathway, compound 11 could suppress the migration and invasion of the ER-negative MDA-MB-231 cell line. Furthermore, compound 11 demonstrated a significant growth suppression of breast cancer xenograft tumours in vivo (inhibition rate 23.58%). The docking results showed that compound 11 could form hydrogen bonds with Glu331 and Arg372 in addition to its hydrophobic interaction with ligand-binding domain. Our data implied that compound 11 represented a novel and effective ERRα inverse agonist, which had broad application prospects in the treatment of triple-negative breast cancer.
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- 2022
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3. Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship, crystal structural characterization and in vivo study
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Peng Wei, Bo Liu, Ruifeng Wang, Yinglei Gao, Lanlan Li, Yuchi Ma, Zhiwei Qian, Yuelei Chen, Maosheng Cheng, Meiyu Geng, Jingkang Shen, Dongmei Zhao, Jing Ai, and Bing Xiong
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors (FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structureactivity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound (35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development. KEY WORDS: Fibroblast growth factor, Tyrosine kinase receptor, Structure-based, Crystallography, Selectivity, Hybrid, 5-Hydrosulfonyl-5H-pyrrolo[2,3-b]pyrazine, Inhibitor
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- 2019
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4. Molecular Dynamics Simulations Based on 1-Phenyl-4-Benzoyl-1-Hydro-Triazole ERRα Inverse Agonists
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Zhipei Gao, Yongli Du, Xiehuang Sheng, and Jingkang Shen
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ERRα ,inverse agonists ,1-phenyl-4-benzoyl-1-hydro-triazole ,MD simulations ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Estrogen-related receptor α (ERRα), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERRα inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERRα. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.
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- 2021
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5. Phage-Display Based Discovery and Characterization of Peptide Ligands against WDR5
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Jiawen Cao, Tiantian Fan, Yanlian Li, Zhiyan Du, Lin Chen, Ying Wang, Xin Wang, Jingkang Shen, Xun Huang, Bing Xiong, and Danyan Cao
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phage display ,biopanning ,WDR5 ,cocrystal structure ,Organic chemistry ,QD241-441 - Abstract
WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein–protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure.
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- 2021
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6. Tetrahydroisoquinolines as novel histone deacetylase inhibitors for treatment of cancer
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Danqi Chen, Aijun Shen, Guanghua Fang, Hongchun Liu, Minmin Zhang, Shuai Tang, Bing Xiong, Lanping Ma, Meiyu Geng, and Jingkang Shen
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Histone deacetylases inhibitor ,Anticancer ,Tetrahydroisoquinoline ,Structure–activity relationship ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Histone acetylation is a critical process in the regulation of chromatin structure and gene expression. Histone deacetylases (HDACs) remove the acetyl group, leading to chromatin condensation and transcriptional repression. HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects. This paper describes our work on the structural determination and structure-activity relationship (SAR) optimization of tetrahydroisoquinoline compounds as HDAC inhibitors. These compounds were tested for their ability to inhibit HDAC 1, 3, 6 and for their ability to inhibit the proliferation of a panel of cancer cell lines. Among these, compound 82 showed the greatest inhibitory activity toward HDAC 1, 3, 6 and strongly inhibited growth of the cancer cell lines, with results clearly superior to those of the reference compound, vorinostat (SAHA). Compound 82 increased the acetylation of histones H3, H4 and tubulin in a concentration-dependent manner, suggesting that it is a broad inhibitor of HDACs.
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- 2016
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7. Virtual Screening and Structure-Based Discovery of Indole Acylguanidines as Potent β-secretase (BACE1) Inhibitors
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Bing Xiong, Yechun Xu, Jingkang Shen, Xin Wang, Lanping Ma, Tiantian Chen, Wuyan Chen, Yiquan Zou, and Li Li
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virtual screening ,docking ,structure-based lead design ,crystal structure ,indole acylguanidine ,Organic chemistry ,QD241-441 - Abstract
Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer’s disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.
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- 2013
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8. Efficient Synthesis of a (Z)-3-Methyleneisoindolin-1-one Library Using Cu(OAc)2•H2O/DBU under Microwave Irradiation
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Li Zhang, Yongliang Zhang, Xin Wang, and Jingkang Shen
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(Z)-3-methyleneisoindolin-1-one ,Cu(OAc)2• ,H2O/DBU ,domino reaction ,cross coupling ,microwave irradiation ,Organic chemistry ,QD241-441 - Abstract
Microwave-promoted efficient synthesis of a (Z)-3-methyleneisoindolin-1-one library from 2-bromobenzamides and terminal alkynes using Cu(OAc)2•H2O/DBU is described. Various benzamide substituents, ring substitutions, including heteroaryl, aryl acetylenes and aliphatic alkynes, could be applied to afford the desired products in good to moderate yield with high stereoselectivity. It is noteworthy that DBU maybe play a dual role as not only the base, but also as a ligand for copper. The reaction is catalyzed by the complex of Cu(OAc)2•H2O and DBU without other additives.
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- 2013
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9. Total Synthesis and Antidepressant Activities of Laetispicine and Its Derivatives
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Jingkang Shen, Shuyi Yao, Shengli Pan, Lin Chen, Xin Wang, Yongliang Zhang, Tao Meng, Hui Xie, and Li Zhang
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laetispicine derivatives ,antidepressant ,total synthesis ,forced swimming test ,Organic chemistry ,QD241-441 - Abstract
The first total synthesis of laetispicine (1a), an amide alkaloid isolated from the stems of Piper laetispicum C.DC (Piperaceae), and the synthesis of some of its derivatives were described. Based on the evaluation of antidepressant activities in the forced swimming test, compounds 1h and 1i were identified as potent and safe antidepressant lead compounds.
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- 2012
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10. Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors
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Alan Jiang, Qiufeng Liu, Ruifeng Wang, Peng Wei, Yang Dai, Xin Wang, Yechun Xu, Yuchi Ma, Jing Ai, Jingkang Shen, Jian Ding, and Bing Xiong
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cancer ,FGFR ,kinase inhibitor ,pyrrolo[2,3-b]pyrazine ,Organic chemistry ,QD241-441 - Abstract
Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5H-pyrrolo[2,3-b]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors. Among them, compound 13 displayed high selectivity and favorable metabolic properties, demonstrating a promising lead for further development.
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- 2018
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11. Preparation of 6-Substituted Quinoxaline JSP-1 Inhibitors by Microwave Accelerated Nucleophilic Substitution
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Jingkang Shen, Jia Li, Jian Liu, Yongliang Zhang, Jingya Li, Xin Wang, Xin Li, Beiying Qiu, and Li Zhang
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Microwave irradiation ,nucleophilic substitution ,6-substituted quinoxalines ,JSP-1. ,Organic chemistry ,QD241-441 - Abstract
A small library of 6-aminoquinoxalines has been prepared by nucleophilic substitution of 6-fluoroquinoxaline with amines and nitrogen-containing heterocycles under computer-controlled microwave irradiation. Some compounds were found to be potent inhibitors of JNK Stimulatory Phosphatase-1 (JSP-1) in an in vitro biological assay.
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- 2006
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12. Discovery and Biological Evaluation of a Series of Pyrrolo[2,3-b]pyrazines as Novel FGFR Inhibitors
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Yan Zhang, Hongchun Liu, Zhen Zhang, Ruifeng Wang, Tongchao Liu, Chaoyun Wang, Yuchi Ma, Jing Ai, Dongmei Zhao, Jingkang Shen, and Bing Xiong
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FGFR1 ,inhibitor ,kinase inhibitor ,pyrazine ,hinge binder ,Organic chemistry ,QD241-441 - Abstract
Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and conducted a chemical optimization. After exploring three parts of the hit compound, we finally discovered a new series of pyrrolo[2,3-b]pyrazine FGFR inhibitors, which contain a novel scaffold and unique molecular shape. We believe that our findings can help others to further develop selective FGFR inhibitors.
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- 2017
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13. Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors
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Zhen Zhang, Dongmei Zhao, Yang Dai, Maosheng Cheng, Meiyu Geng, Jingkang Shen, Yuchi Ma, Jing Ai, and Bing Xiong
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cancer ,FGFR ,inhibitor ,4-substituted-1H-indazole ,Organic chemistry ,QD241-441 - Abstract
Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-phenyl-1H-indazole-4-carboxamide (10a) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-4-carboxamide (13a) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC50 value of about 30.2 nM.
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- 2016
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14. CaMKKβ is involved in AMP-activated protein kinase activation by baicalin in LKB1 deficient cell lines.
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Ying Ma, Fuzhen Yang, Ying Wang, Zhiyan Du, Daihua Liu, Hongxia Guo, Jingkang Shen, and Hongli Peng
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Medicine ,Science - Abstract
AMP-activated protein kinase (AMPK) plays an important role in mediating energy metabolism and is controlled mainly by two upstream kinases, LKB1 or Ca(2+)/calmodulin-dependent protein kinase kinase-β (CaMKKβ). Previously, we found that baicalin, one of the major flavonoids in a traditional Chinese herb medicine, Scutellaria baicalensis, protects against the development of hepatic steatosis in rats feeding with a high-fat diet by the activation of AMPK, but, the underlying mechanism for AMPK activation is unknown. Here we show that in two LKB1-deficient cells, HeLa and A549 cells, baicalin activates AMPK by α Thr-172 phosphorylation and subsequent phosphorylation of its downstream target, acetyl CoA carboxylase, at Ser-79, to a similar degree as does in HepG2 cells (that express LKB1). Pharmacologic inhibition of CaMKKβ by its selective inhibitor STO-609 markedly inhibits baicalin-induced AMPK activation in both HeLa and HepG2 cells, indicating that CaMKKβ is the responsible AMPK kinase. We also show that treatment of baicalin causes a larger increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), although the maximal level of [Ca(2+)](i) is lower in HepG2 cells compared to HeLa cells. Chelation of intracellular free Ca(2+) by EDTA and EGTA, or depletion of intracellular Ca(2+) stores by the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin abrogates baicalin-induced activation of AMPK in HeLa cells. Neither cellular ATP nor the production of reactive oxygen species is altered by baicalin. Finally, in HeLa cells, baicalin treatment no longer decreases intracellular lipid accumulation caused by oleic acid after inhibition of CaMKKβ by STO-609. These results demonstrate that a potential Ca(2+)/CaMKKβ dependent pathway is involved in the activation of AMPK by baicalin and suggest that CaMKKβ likely acts as an upstream kinase of AMPK in response to baicalin.
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- 2012
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15. (2R,6S)-tert-Butyl 2-(benzhydrylcarbamoyl)-6-methylmorpholine-4-carboxylate
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Haiyang Wang, Guangxin Xia, Xuejun Liu, and Jingkang Shen
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Crystallography ,QD901-999 - Abstract
The title compound, C24H30N2O4, was obtained by the reaction of (2R,6S)-4-(tert-butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid with diphenylmethanamine in dimethylformamide solution. The morpholine ring is in a chair conformation. In the crystal, weak intermolecular C—H...O hydrogen bonds link molecules into chains along the b axis.
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- 2011
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16. (S)-tert-Butyl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate
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Lin Liu, Guangxin Xia, Xuejun Liu, Jieshu Xie, and Jingkang Shen
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Crystallography ,QD901-999 - Abstract
The title compound, C18H23N3O3, crystallized with two independent molecules (A and B) in the asymmetric unit. The phenyl ring and the 1,2,4-oxadiazole ring are inclined to one another by 19.9 (3)° in molecule A and 7.3 (3)° in molecule B. The absolute structure of the title compound was referred to the transfered chiral center (S) of one of the starting reactants. In the crystal, A molecules are linked by C—H...N interactions involving the two oxadiazole N atoms.
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- 2010
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17. Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for treatment of Nectin-4-expressing Cancers
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Wei Zhou, Peng Fang, Dongan Yu, Hongyuan Ren, Meng You, Long Yin, Fei Mei, Huikai Zhu, Zhenzhen Wang, Hui Xu, Yuxia Cao, Xiaowei Sun, Xiaohong Xu, Jianjun Bi, Jin Wang, Lanping Ma, Xin Wang, Lin Chen, Yongliang Zhang, Xiaowei Cen, Xi Zhu, Liguang Lou, Datao Liu, Xiaoding Tan, Jinliang Yang, Tao Meng, and Jingkang Shen
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Cancer Research ,Oncology - Abstract
Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4-targeting antibody drug conjugate approved by the US Food and Drug Administration for treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematological toxic side effects are common in nectin-4-targeted therapy, which frequently results in dose reduction and/or treatment termination. Thus, we designed a second generation nectin-4-specific drug, 9MW2821, based on interchain-disulfide drug conjugate technology. This novel drug contained a site-specifically conjugated humanized antibody and the cytotoxic moiety monomethyl auristatin E. The homogenous drug-antibody ratio and novel linker chemistry of 9MW2821 increased the stability of conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. In preclinical evaluation, 9MW2821 exhibited nectin-4 specific cell binding, efficient internalization, bystander killing, and equivalent or superior antitumor activity compared with EV in both cell-line-derived xenograft and patient-derived xenograft models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest non-severely toxic dose in monkey toxicological studies was 6 mg/kg, with milder adverse events compare to EV. Overall, 9MW2821 is a nectin-4-directed, investigational antibody-drug conjugate based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 antibody-drug conjugate is being investigated in a Phase I/II clinical trial (NCT05216965) in patients with advanced solid tumors.
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- 2023
18. Advances in Medicinal Chemistry of Estrogen-related receptor alpha (ERRα) inverse agonists
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Yongli Du, Haibin Zhang, Yong Zheng, Huiting Lv, Zhijia Yan, Ning Dong, Yaling Zhu, and Jingkang Shen
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Drug Discovery ,General Medicine - Abstract
Abstract: Estrogen-related receptor alpha (ERRα), a member of the nuclear receptor superfamily, is strongly expressed in breast cancer cells. Its overexpression is associated with poor prognosis in triple-negative breast cancer (TNBC). ERRα expression could be inhibited by the downregulation of upstream oncogenic growth factors mTOR, HER2, and PI3K. Low expression of ERRα could suppress the migration and angiogenesis of tumor cells by inhibiting the activity of its downstream signals VEGF and WNT11. Studies have confirmed that ERRα inverse agonists can inhibit ERRα expression to treat breast cancer. Inverse agonists of ERRα could disrupt the interactions of ERRα with its coactivators and inhibit tumor development. Existing ERRα inverse agonists have shown moderate efficacy in inhibiting the growth of breast cancer cells. Clinical inverse agonists of ERRα have not been found in the literature. This review focuses on the research progress and the structure-activity relationship of ERRα inverse agonists, providing guidance for the research and discovery of new anti-tumor compounds for TNBC.
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- 2023
19. Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor
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Daisuke Iijima, Hiroshi Sugama, Yoichi Takahashi, Miki Hirai, Yuko Togashi, Jianshu Xie, Jingkang Shen, Ying Ke, Hidenori Akatsuka, Takayuki Kawaguchi, Kei Takedomi, Akiko Kashima, Masashi Nishio, Yosuke Inui, Hikaru Yoneda, Guangxin Xia, and Toru Iijima
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Renin-Angiotensin System ,Fumarates ,Morpholines ,Hypertension ,Renin ,Drug Discovery ,Humans ,Molecular Medicine ,Amides ,Antihypertensive Agents - Abstract
Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of500 and discovered the promising 2-carbamoyl morpholine derivative
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- 2022
20. Data from Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models
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Meiyu Geng, Jian Ding, Jingkang Shen, Bing Xiong, Yuchi Ma, Yinglei Gao, Yiming Sun, Yi Su, Xinying Yang, Yanyan Shen, Yong Xi, Yinchun Ji, Xia Peng, Yi Chen, and Jing Ai
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Because the receptor tyrosine kinase c-Met plays a critical role in tumor growth, metastasis, tumor angiogenesis, and drug resistance, the c-Met axis represents an attractive therapeutic target. Herein, we report the first preclinical characterization of SCC244, a novel, potent, and highly selective inhibitor of c-Met kinase. SCC244 showed subnanomolar potency against c-Met kinase activity and high selectivity versus 312 other tested protein kinases, making it one of the most selective c-Met inhibitors described to date. Moreover, this inhibitor profoundly and specifically inhibits c-Met signal transduction and thereby suppresses the c-Met–dependent neoplastic phenotype of tumor and endothelial cells. In xenografts of human tumor cell lines or non–small cell lung cancer and hepatocellular carcinoma patient-derived tumor tissue driven by MET aberration, SCC244 administration exhibits robust antitumor activity at the well-tolerated doses. In addition, the in vivo antitumor activity of SCC244 involves the inhibition of c-Met downstream signaling via a mechanism of combined antiproliferation and antiangiogenic effects. The results of the current study provide a strong foundation for the clinical investigation of SCC244 in patients with tumors harboring c-Met pathway alterations. Mol Cancer Ther; 17(4); 751–62. ©2017 AACR.
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- 2023
21. Supplementary Figures from Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody–Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function
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Ker Yu, Jingkang Shen, Xin Wang, Zhiqiang Ren, Xuesai Zhang, Ying Cong, Jinpeng Pei, Lanping Ma, Tao Meng, Yun Xing, Liang Liu, and Rui Jin
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Supplementary Figures and Tables
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- 2023
22. Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis
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Bi-xi Tang, Jia Li, Qi Wang, Yueyue Yang, Bing Xiong, Rongrong Xie, Danqi Chen, Jingkang Shen, Cong Li, Ying Dong, Yue Dong, Lin Chen, Yinchun Ji, Huanyu Shi, Li-Wei Zhou, Tan Qian, Dan-Dan Sun, Yi Zang, and Menglan Luo
- Subjects
Drug ,DDR1 ,Kinase ,business.industry ,media_common.quotation_subject ,Pharmacology ,medicine.disease ,Idiopathic pulmonary fibrosis ,Drug development ,In vivo ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor ,business ,Discoidin domain ,media_common - Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3‒5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound 47 would be a promising candidate for further drug development.
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- 2022
23. Molecular modeling studies of [4-(3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine-based CDK4 inhibitors
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Yongli Du, Jingkang Shen, Xiehuang Sheng, Han Lv, and Zhipei Gao
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Pharmacology ,endocrine system diseases ,integumentary system ,010304 chemical physics ,Molecular model ,Chemistry ,Field analysis ,01 natural sciences ,Combinatorial chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Molecular dynamics ,0302 clinical medicine ,CDK4 Inhibitor ,030220 oncology & carcinogenesis ,0103 physical sciences ,Drug Discovery ,Molecular Medicine ,Amine gas treating ,biological phenomena, cell phenomena, and immunity ,neoplasms ,Abemaciclib - Abstract
Aim: CDK4 is a promising target for breast cancer therapy. This study aimed to explore the structure–activity relationship of CDK4 inhibitor abemaciclib analogs and design potent CDK4 inhibitors for breast cancer treatment. Methods & results: A faithful 3D quantitative structure–activity relationship model was established by molecular docking, comparative molecular field analysis and comparative molecular similarity index analysis based on 56 abemaciclib analogs. Molecular dynamics simulation studies revealed the key residues of the interaction between CDK4 and inhibitors. Four novel inhibitors with satisfactory predicted binding affinity to CDK4 were designed. Conclusion: The 3D quantitative structure–activity relationship and molecular dynamics simulation studies provide valuable insight into the development of novel CDK4 inhibitors.
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- 2021
24. Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells
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Peng Wang, Danyan Cao, Xin Hu, Bing Xiong, Ze-Hong Miao, Mengzhu Xue, Yuwei Liu, Ying Wang, Jingkang Shen, and Lihuai Qin
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0106 biological sciences ,Drug resistance ,Biology ,01 natural sciences ,BET inhibitor ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Carbonyl Reductase (NADPH) ,Wnt Signaling Pathway ,beta Catenin ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Liver Neoplasms ,Wnt signaling pathway ,medicine.disease ,In vitro ,Notum ,Bromodomain ,Gene Expression Regulation, Neoplastic ,Cancer research ,Liver cancer ,010606 plant biology & botany - Abstract
The Bromodomain and Extra-terminal domain (BET) proteins are promising targets in treating cancers. Although BET inhibitors have been in clinical trials, they are limited by lacking of suitable biomarkers to indicate drug responses in different cancers. Here we identify DHRS2, ETV4 and NOTUM as potential biomarkers to indicate drug resistance in liver cancer cells of a recently discovered BET inhibitor, Hjp-6-171. Furthermore, we confirm that reactivation of WNT pathway, the target of NOTUM, contributes to the drug sensitivity restoration in Hjp-6-171 resistant cells. Specially, combinations of Hjp-6-171 and a GSK3β inhibitor CHIR-98014 show remarkable therapeutic effects in vitro and in vivo. Integrating RNA-seq and ChIP-seq data, we reveal the expression signature of β-catenin regulated genes is contrary in sensitive cells to that in resistant cells. We propose WNT signaling molecules such as β-catenin and ETV4 to be candidate biomarkers to indicate BET inhibitor responses in liver cancer patients.
- Published
- 2021
25. Discovery of Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors
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Daisuke Iijima, Hiroshi Sugama, Nobumasa Awai, Yoichi Takahashi, Yuko Togashi, Tohru Takebe, Jianshu Xie, Jingkang Shen, Ying Ke, Hidenori Akatsuka, Takayuki Kawaguchi, Kei Takedomi, Akiko Kashima, Masashi Nishio, Yosuke Inui, Hikaru Yoneda, Guangxin Xia, and Toru Iijima
- Subjects
Organic Chemistry ,Drug Discovery ,Biochemistry - Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of500. The representative compound
- Published
- 2022
26. Water PMF for predicting the properties of water molecules in protein binding site.
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Mingyue Zheng, Yanlian Li, Bing Xiong, Hualiang Jiang, and Jingkang Shen
- Published
- 2013
- Full Text
- View/download PDF
27. Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases
- Author
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Xin Wang, Lin Chen, Jie Mou, Dong-Sheng Pei, Tiantian Fan, Huijie Zhang, Jingkang Shen, Bing Xiong, Weicong Chen, Danqi Chen, Kaikai Lv, Danyan Cao, and Yanlian Li
- Subjects
0303 health sciences ,BRD4 ,Drug discovery ,Chemistry ,Rational design ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Bromodomain ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Molecular Medicine ,Structure–activity relationship ,Cyclin-dependent kinase 9 ,Pharmacophore ,Lead compound ,030304 developmental biology - Abstract
Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50 = 12.7 nM) and CDK9 (IC50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.
- Published
- 2020
28. Knowledge-Based Scoring Functions in Drug Design: 2. Can the Knowledge Base Be Enriched?
- Author
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Qiancheng Shen, Bing Xiong, Mingyue Zheng, Xiaomin Luo, Cheng Luo, Xian Liu, Yun Du, Jing Li, Weiliang Zhu, Jingkang Shen, and Hualiang Jiang
- Published
- 2011
- Full Text
- View/download PDF
29. Knowledge-Based Scoring Functions in Drug Design. 1. Developing a Target-Specific Method for Kinase-Ligand Interactions.
- Author
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Mengzhu Xue, Mingyue Zheng, Bing Xiong, Yanlian Li, Hualiang Jiang, and Jingkang Shen
- Published
- 2010
- Full Text
- View/download PDF
30. The Structure of MT189-Tubulin Complex Provides Insights into Drug Design
- Author
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Yamei Yu, Qiang Chen, Wenyue Zheng, Zhongping Li, Chengyong Wu, Lanping Ma, Jingkang Shen, Jinliang Yang, Lingling Ma, and Tao Meng
- Subjects
0301 basic medicine ,Drug ,Tubulin complex ,Chemistry ,media_common.quotation_subject ,Structural protein ,Pharmaceutical Science ,macromolecular substances ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Drug Discovery ,Biophysics ,Molecular Medicine ,media_common - Abstract
Background: Drugs that interfere with microtubule dynamics are used widely in cancer chemotherapy. Microtubules are composed of αβ-tubulin heterodimers, and the colchicine binding site of tubulin is an important pocket for designing tubulin polymerization inhibitors. We have previously designed and synthesized a series of colchicine binding site inhibitors (CBSIs). However, these compounds showed no anticancer activity in vivo. Then, we have used a deconstruction approach to obtain a new derivative MT189, which showed in vivo anticancer activity. Methods: We crystallized a protein complex including two tubulins, one stathmin-like domain of RB3 and one tubulin tyrosine ligase, and soaked MT189 into the crystals. We collected the diffraction data and determined the tubulin-MT189 structure to 2.8 Å. Results: Here, we report the crystal structure of tubulin complexed with MT189, elucidate how the small-molecular agent binds to tubulin and inhibits microtubule assembly, and explain previous results of the structure-activity-relationship studies. Conclusion: The tubulin-MT189 complex structure reveals the interactions between this agent and tubulin and provides insights into the design of new derivatives targeting the colchicine binding site.
- Published
- 2019
31. Designing of novel ERRγ inverse agonists by molecular modeling studies of docking and 3D-QSAR on hydroxytamoxifen derivatives
- Author
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Yongli Du, Jingkang Shen, and Rui Li
- Subjects
Agonist ,Quantitative structure–activity relationship ,Molecular model ,010405 organic chemistry ,Chemistry ,medicine.drug_class ,Organic Chemistry ,Pharmacology toxicology ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Docking (molecular) ,medicine ,Inverse agonist ,General Pharmacology, Toxicology and Pharmaceutics - Abstract
ERRγinverse agonist is a powerful therapeutic target for the treatment of cancers and certain metabolic disorders. Until now, only GSK5814 was reported as selective ERRγinverse agonist. So 60 newly hydroxytamoxifen analogues were selected to perform molecular docking and 3D-QSAR study to design more selective inverse agonist of ERRγ. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value, demonstrated that bulky, hydrophobic and negative electrostatic substitutions are preferred at R2 position, and introducing hydrophilic and H-bond donor and acceptor groups at R1 and R4 positions is greatly important for improving binding activities. The obtained information will be useful to provide clues for rationally designing novel and high potency ERRγinverse agonists.
- Published
- 2019
32. Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1
- Author
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Qi, Wang, Bixi, Tang, Dandan, Sun, Ying, Dong, Yinchun, Ji, Huanyu, Shi, Liwei, Zhou, Yueyue, Yang, Menglan, Luo, Qian, Tan, Lin, Chen, Yue, Dong, Cong, Li, Rongrong, Xie, Yi, Zang, Jingkang, Shen, Bing, Xiong, Jia, Li, and Danqi, Chen
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3-5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor
- Published
- 2021
33. Molecular modeling studies of [4-(3
- Author
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Han, Lv, Yongli, Du, Xiehuang, Sheng, Zhipei, Gao, and Jingkang, Shen
- Subjects
Models, Molecular ,Molecular Structure ,Cyclin-Dependent Kinase 4 ,Humans ,Quantitative Structure-Activity Relationship ,Protein Kinase Inhibitors - Published
- 2021
34. Molecular Dynamics Simulations Based on 1-Phenyl-4-Benzoyl-1-Hydro-Triazole ERRα Inverse Agonists
- Author
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Jingkang Shen, Yongli Du, Zhipei Gao, and Xiehuang Sheng
- Subjects
0301 basic medicine ,Drug Inverse Agonism ,Binding free energy ,Stereochemistry ,Triazole ,Molecular Dynamics Simulation ,01 natural sciences ,Catalysis ,Article ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Molecular dynamics ,0103 physical sciences ,Inverse agonist ,Physical and Theoretical Chemistry ,Receptor ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,MD simulations ,010304 chemical physics ,Hydrogen bond ,Organic Chemistry ,ERRα ,Biological activity ,General Medicine ,Computer Science Applications ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Receptors, Estrogen ,chemistry ,1-phenyl-4-benzoyl-1-hydro-triazole ,inverse agonists - Abstract
Estrogen-related receptor α (ERRα), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERRα inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERRα. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.
- Published
- 2021
35. A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction
- Author
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Chang-Qing Tian, Ying-Qing Wang, Jianping Hu, Danqi Chen, Huan Xiajuan, Shanshan Song, Ze-Hong Miao, Bing Xiong, Tao Meng, Mohammadali Soleimani Damaneh, Jingkang Shen, and Yue-Lei Chen
- Subjects
0301 basic medicine ,BRD4 ,Programmed cell death ,Cell cycle checkpoint ,Mice, Nude ,Apoptosis ,Resting Phase, Cell Cycle ,Epigenesis, Genetic ,BET inhibitor ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Animals ,Humans ,Pharmacology (medical) ,Cell Proliferation ,Pharmacology ,Mice, Inbred BALB C ,Cell Death ,Cell growth ,Chemistry ,G1 Phase ,Proteins ,Cell Cycle Checkpoints ,Cell cycle ,Xenograft Model Antitumor Assays ,Bromodomain ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,A549 Cells ,030220 oncology & carcinogenesis ,PC-3 Cells ,Cancer research ,HT29 Cells - Abstract
The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G0/G1 phase. However, compound 171 only has a quite limited effect on apoptosis, in considering that apoptosis was only observed at doses greater than 50 μM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.
- Published
- 2019
36. Inhibition of the BET family reduces its new target gene IDO1 expression and the production of l-kynurenine
- Author
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Ze-Hong Miao, Hua-Dong Chen, Lin Chen, Bing Xiong, Jianping Hu, Chang-Qing Tian, Huan Xiajuan, Ying-Qing Wang, and Jingkang Shen
- Subjects
0301 basic medicine ,Cancer Research ,Gene Expression ,Cancer immunotherapy ,Cell Cycle Proteins ,RNA polymerase II ,Histones ,Mice ,0302 clinical medicine ,Gene expression ,Promoter Regions, Genetic ,Kynurenine ,Mice, Inbred BALB C ,Sulfonamides ,biology ,Chemistry ,lcsh:Cytology ,Acetylation ,hemic and immune systems ,Tumor Burden ,030220 oncology & carcinogenesis ,Female ,BRD4 ,Pyridones ,Immunology ,Mice, Nude ,HL-60 Cells ,chemical and pharmacologic phenomena ,Transfection ,Article ,BET inhibitor ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Histone H3 ,Animals ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,RNA, Messenger ,lcsh:QH573-671 ,Messenger RNA ,RNA ,Cell Biology ,Xenograft Model Antitumor Assays ,Molecular biology ,Bromodomain ,030104 developmental biology ,A549 Cells ,biology.protein ,Immunosuppression ,HeLa Cells ,Transcription Factors - Abstract
The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to l-kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1. Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of l-kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced l-kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers.
- Published
- 2019
37. Stereoselective N-glycosylation with N4-acyl cytosines and efficient synthesis of gemcitabine
- Author
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Jun-Da Cen, Jiadeng Tang, Dongmei Zhao, Tongchao Liu, Chen Yabin, Jingkang Shen, Bing Xiong, Jianpeng Liang, Yue-Lei Chen, and Xiaowen Wang
- Subjects
Anomer ,Glycosylation ,Pyrimidine ,010405 organic chemistry ,Chemistry ,Mesylate ,Stereochemistry ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Gemcitabine ,0104 chemical sciences ,carbohydrates (lipids) ,chemistry.chemical_compound ,N-linked glycosylation ,Drug Discovery ,medicine ,Nucleoside ,Cytosine ,medicine.drug - Abstract
Through systematical comparison of various N4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta-stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N4-Bz cytosine and anomeric mixture of 2,2‘-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine.
- Published
- 2019
38. Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma
- Author
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Xia Peng, Meiyu Geng, Qi Wang, Xin Wang, Lin Chen, Yuchen Jiang, Zuhao Guo, Yue-Lei Chen, Yinglei Gao, Danqi Chen, Yang Dai, Huanyu Shi, Jingkang Shen, Yinchun Ji, Bing Xiong, and Jing Ai
- Subjects
Indazoles ,Lung Neoplasms ,medicine.medical_treatment ,Antineoplastic Agents ,01 natural sciences ,Targeted therapy ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Discoidin Domain Receptor 2 ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Protein Kinase Inhibitors ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Indazole ,010405 organic chemistry ,Kinase ,Fibroblast growth factor receptor 1 ,Organic Chemistry ,General Medicine ,medicine.disease ,0104 chemical sciences ,Enzyme ,chemistry ,Drug development ,Fibroblast growth factor receptor ,Carcinoma, Squamous Cell ,Cancer research ,Heterografts ,Adenocarcinoma - Abstract
Although lung adenocarcinoma patients have benefited from the development of targeted therapy, patients with lung squamous cell carcinoma (SqCC) have no effective treatment due to the complexity and heterogeneity of the disease. Therefore, basing on the genetic analysis of mutations in lung squamous cell carcinoma to design multi-target inhibitors represents a potential strategy for the medical treatment. In this study, through screening an in-house focused library, we identified an interesting indazole scaffold. And following with binding analysis, we elaborated the structure-activity relationship of this hit compound by optimizing four parts guided by the DDR2 enzymatic assay, which resulted in a potent lead compound 10a. We conducted further optimization of dual enzymatic inhibitions towards FGFR1 and DDR2, two important kinases in lung squamous cell carcinoma. Finally, from the cellular antiproliferative activity tests and in vivo pharmacokinetic test, 3-substituted indazole derivative 11k was found to be a promising candidate and subjected to in vivo pharmacology study with the mouse xenograft models, demonstrating profound anti-tumor efficacy. Additional in vitro druglike assessment reinforced that compound 11k could be valuable for SqCC drug development.
- Published
- 2019
39. Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship, crystal structural characterization and in vivo study
- Author
-
Yuchi Ma, Meiyu Geng, Peng Wei, Bing Xiong, Dongmei Zhao, Lanlan Li, Maosheng Cheng, Jing Ai, Zhiwei Qian, Yinglei Gao, Jingkang Shen, Yue-Lei Chen, Ruifeng Wang, and Bo Liu
- Subjects
Original article ,Inhibitor ,Structure-based ,Fibroblast growth factor ,Tyrosine kinase receptor ,Receptor tyrosine kinase ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,5-Hydrosulfonyl-5H-pyrrolo[2,3-b]pyrazine ,Structure–activity relationship ,Selectivity ,General Pharmacology, Toxicology and Pharmaceutics ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Crystallography ,biology ,Chemistry ,lcsh:RM1-950 ,In vitro ,Hybrid ,lcsh:Therapeutics. Pharmacology ,Enzyme ,Biochemistry ,Fibroblast growth factor receptor ,030220 oncology & carcinogenesis ,biology.protein ,Signal transduction - Abstract
Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors (FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure—activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound (35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development., Graphical abstract With the guidance of the crystal structure, we discovered a series of selective FGFR inhibitors bearing 5H-pyrrolo[2,3-b]pyrazine scaffold. After considerable efforts to improve the metabolic stability and pharmacokinetic properties, finally, we obtained a potent and active compound 35 showing in vivo efficacy in xenograft mouse model.fx1
- Published
- 2018
40. Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers
- Author
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Yongliang Zhang, Lanping Ma, Shanshan Song, Ze-Hong Miao, Ting Yu, Ning Zhang, Jingkang Shen, Bing Xiong, Xu-Bin Bao, Tao Meng, Jin-Xue He, and Meng-Zhu Li
- Subjects
0301 basic medicine ,Male ,Cell cycle checkpoint ,DNA Repair ,DNA damage ,Cell Survival ,Mice, Nude ,Antineoplastic Agents ,Poly(ADP-ribose) Polymerase Inhibitors ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Pharmacology (medical) ,Pharmacology ,BRCA2 Protein ,Cell growth ,BRCA1 Protein ,Xenograft Model Antitumor Assays ,Rats ,G-Quadruplexes ,030104 developmental biology ,Oncology ,chemistry ,Apoptosis ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,PARP inhibitor ,Cancer cell ,Cancer research ,Phthalazines ,Homologous recombination ,DNA - Abstract
G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.
- Published
- 2021
41. Phage-Display Based Discovery and Characterization of Peptide Ligands against WDR5
- Author
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Zhiyan Du, Tiantian Fan, Xun Huang, Jingkang Shen, Bing Xiong, Xin Wang, Ying Wang, Danyan Cao, Jiawen Cao, Yanlian Li, and Lin Chen
- Subjects
Phage display ,cocrystal structure ,WDR5 ,Pharmaceutical Science ,Biopanning ,Ligands ,Peptides, Cyclic ,Chromatin remodeling ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Organic chemistry ,Peptide Library ,Drug Discovery ,Humans ,Epigenetics ,Physical and Theoretical Chemistry ,biopanning ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Chemistry ,Ligand binding assay ,Organic Chemistry ,Intracellular Signaling Peptides and Proteins ,Cyclic peptide ,Histone ,Biochemistry ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,phage display ,Protein Binding - Abstract
WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein–protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure.
- Published
- 2020
42. Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1
- Author
-
Kaikai, Lv, Weicong, Chen, Danqi, Chen, Jie, Mou, Huijie, Zhang, Tiantian, Fan, Yanlian, Li, Danyan, Cao, Xin, Wang, Lin, Chen, Jingkang, Shen, Dongsheng, Pei, and Bing, Xiong
- Subjects
Models, Molecular ,Cell Cycle Proteins ,Cyclin-Dependent Kinase 9 ,Mice ,Structure-Activity Relationship ,Protein Domains ,Cell Line, Tumor ,Drug Design ,Quinoxalines ,Drug Discovery ,Animals ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,Transcription Factors - Abstract
Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1
- Published
- 2020
43. Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function
- Author
-
Pei Jinpeng, Ker Yu, Jin Rui, Zhiqiang Ren, Xin Wang, Yun Xing, Lanping Ma, Liang Liu, Xuesai Zhang, Jingkang Shen, Ying Cong, and Tao Meng
- Subjects
0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Immunoconjugates ,Lung Neoplasms ,medicine.medical_treatment ,T-Lymphocytes ,GPI-Linked Proteins ,Effector T-Lymphocyte ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Antineoplastic Agents, Immunological ,Glioma ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Molecular Targeted Therapy ,Lung cancer ,Cytotoxicity ,5'-Nucleotidase ,Cell Proliferation ,Tumor microenvironment ,biology ,Dose-Response Relationship, Drug ,Neovascularization, Pathologic ,business.industry ,Receptors, IgG ,Immunotherapy ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,biology.protein ,Cancer research ,Antibody ,business - Abstract
Although tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50
- Published
- 2020
44. Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors
- Author
-
Lin Chen, Bing Xiong, Danyan Cao, Chang-Qing Tian, Ting Yu, Jingkang Shen, Yanlian Li, Shanshan Song, Xin Wang, Danqi Chen, Lihuai Qin, Mohammadali Soleimani Damaneh, Jianping Hu, Jian Li, Ze-Hong Miao, Huan Xiajuan, Kaikai Lv, Tao Meng, and Ying-Qing Wang
- Subjects
Male ,BRD4 ,hERG ,Protein domain ,Mice, Nude ,Antineoplastic Agents ,Cell Cycle Proteins ,Mice, SCID ,Pharmacology ,Crystallography, X-Ray ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,Protein Domains ,In vivo ,Neoplasms ,Drug Discovery ,Animals ,Humans ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Mice, Inbred BALB C ,Mice, Inbred ICR ,biology ,Molecular Structure ,Chemistry ,Drug discovery ,Nuclear Proteins ,Proteins ,0104 chemical sciences ,Bromodomain ,010404 medicinal & biomolecular chemistry ,Drug Design ,biology.protein ,Microsomes, Liver ,Molecular Medicine ,Peptides ,Linker ,Lead compound ,Neoplasm Transplantation ,Transcription Factors - Abstract
BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.
- Published
- 2019
45. New microtubulin inhibitor MT189 suppresses angiogenesis via the JNK-VEGF/VEGFR2 signaling axis
- Author
-
Wei Wang, Ze-Hong Miao, Lanping Ma, Tao Meng, Ying-Qing Wang, Lin Xu, Jingkang Shen, and Linjiang Tong
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,Cancer Research ,Pyridines ,Angiogenesis ,Chick Embryo ,Cell Line ,Focal adhesion ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Secretion ,Cell adhesion ,Cells, Cultured ,Paxillin ,Cell Proliferation ,biology ,Chemistry ,Imidazoles ,JNK Mitogen-Activated Protein Kinases ,Vinculin ,Vascular Endothelial Growth Factor Receptor-2 ,Tubulin Modulators ,Rats ,Cell biology ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Microvessels ,biology.protein ,Phosphorylation ,HeLa Cells ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src - Abstract
The microtubulin inhibitor MT189 possesses anticancer activity and has been shown to overcome multidrug resistance. Here, we report that MT189 also inhibits angiogenesis. MT189 inhibited the proliferation, migration and differentiation of endothelial cells, with or without VEGF stimulation, and suppressed microvessel formation ex vivo and in vivo. MT189 reduced VEGF expression and secretion in both tumor and endothelial cells, under either hypoxic or normoxic conditions. The activation of VEGFR2 and downstream Src was thus abrogated in the MT189-treated endothelial cells. MT189 subsequently stabilized endothelial cell-cell junctions consist of VE-cadherin, β-catenin, vinculin, and actin. MT189 also disrupted endothelial cell-matrix junctions by inhibiting the turnover of focal adhesions containing FAK, paxillin, vinculin, and actin. Inhibition of JNK reversed MT189-mediated inhibition of endothelial migration and differentiation, JNK activation, the reduction of VEGF expression and secretion, and the decrease of Src and FAK phosphorylation. These results indicate that MT189 suppresses angiogenesis by reducing endothelial proliferation, migration, and differentiation via the JNK-VEGF/VEGFR2 signaling axis. Together with our previous report showing that MT189 exhibited anticancer activity via the JNK-MCL-1 pathway, these new findings further support MT189-based drug development for cancer therapy.
- Published
- 2018
46. Discovery of novel high potent and cellular active ADC type PTP1B inhibitors with selectivity over TC-PTP via modification interacting with C site
- Author
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Yanhui Zhang, Qunyi Li, Yongli Du, Jingkang Shen, and Ling Hao
- Subjects
0301 basic medicine ,Cellular activity ,Stereochemistry ,Negative regulator ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Humans ,Structure–activity relationship ,Enzyme Inhibitors ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,Pharmacology ,Protein Tyrosine Phosphatase, Non-Receptor Type 2 ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,General Medicine ,Molecular Docking Simulation ,Insulin receptor ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Selectivity ,hormones, hormone substitutes, and hormone antagonists - Abstract
PTP1B serving as a key negative regulator of insulin signaling is a novel target for type 2 diabetes and obesity. Modification at ring B of N-{4-[(3-Phenyl-ureido)-methyl]-phenyl}-methane-sulfonamide template to interact with residues Arg47 and Lys41 in the C site of PTP1B by molecular docking aided design resulted in the discovery of a series of novel high potent and selective inhibitors of PTP1B. The structure activity relationship interacting with the C site of PTP1B was well illustrated. Compounds 8 and 18 were shown to be the high potent and most promising PTP1B inhibitors with cellular activity and great selectivity over the highly homologous TCPTP and other PTPs.
- Published
- 2018
47. Efficient syntheses of alpha- and beta-C-nucleosides and the origin of anomeric selectivity
- Author
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Weiliang Zhu, Dongmei Zhao, Huanming Ren, Zhengdan Zhu, Yue-Lei Chen, Tongchao Liu, Jingkang Shen, Guohua Chen, Chen Yabin, Maosheng Cheng, and Bing Xiong
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Anomer ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Alpha (ethology) ,010402 general chemistry ,01 natural sciences ,Silane ,0104 chemical sciences ,chemistry.chemical_compound ,Sugar moiety ,C nucleosides ,Selectivity ,Beta (finance) ,Protecting group - Abstract
C-Nucleosides constitute a valuable class of compounds in biological and medicinal chemistry studies. We report herein a new and efficient synthesis of both alpha- and beta-C-nucleosides with high anomeric selectivity from N6-Boc protected purine analogues. The synthetic approach features a carefully designed lithiation and silane reduction sequence. The anomeric stereochemistry outcome is dictated by the protecting group of sugar lactones. Computational studies suggest that previously neglected interactions between partially positively-charged silane and the substitutions on a sugar moiety play important roles in the anomeric selectivity of silane-mediated C-nucleoside synthesis.
- Published
- 2018
48. Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor
- Author
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Ze-Hong Miao, Tao Meng, Jianping Hu, Xin Wang, Lin Xu, Yue-Lei Chen, Mohammadali Soleimani Damaneh, Shanshan Song, Bing Xiong, Ying-Qing Wang, Jingkang Shen, Danyan Cao, and Yanlian Li
- Subjects
0301 basic medicine ,BRD4 ,Stereochemistry ,Mice, Nude ,Antineoplastic Agents ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,PLK1 ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Quinoxalines ,Drug Discovery ,Animals ,Humans ,P-TEFb ,Protein Kinase Inhibitors ,Cell Proliferation ,Pharmacology ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Kinase ,Organic Chemistry ,Nuclear Proteins ,Neoplasms, Experimental ,General Medicine ,Xenograft Model Antitumor Assays ,Combinatorial chemistry ,Bromodomain ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Female ,Fluorescence anisotropy ,Transcription Factors - Abstract
Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin-2(1H)-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 μM. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model.
- Published
- 2017
49. Quantum chemistry study on the interaction of the exogenous ligands and the catalytic zinc ion in matrix metalloproteinases
- Author
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Feng Cheng, Ruihao Zhang, Xiaomin Luo, Jianhua Shen, Xin Li, Jiande Gu, Weiliang Zhu, Jingkang Shen, Sagi, Irit, Ruyun Ji, Kaixian Chen, and Hualiang Jiang
- Subjects
Chemistry, Physical and theoretical -- Research ,Quantum chemistry -- Research ,Ligands -- Physiological aspects ,Zinc -- Physiological aspects ,Metal ions -- Physiological aspects ,Metalloenzymes -- Physiological aspects ,Chemicals, plastics and rubber industries - Published
- 2002
50. Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma
- Author
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Hui Zhao, Jin Rui, Qingrou Li, Lanping Ma, Jingkang Shen, Xuesai Zhang, Jianchang Qian, Tao Meng, and Ker Yu
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Antibody-drug conjugate ,Vimentin ,Malignancy ,Metastasis ,antibody-drug conjugate ,03 medical and health sciences ,Tissue factor ,0302 clinical medicine ,pancreatic adenocarcinoma ,Medicine ,metastasis ,Triple-negative breast cancer ,biology ,business.industry ,medicine.disease ,tissue factor ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,triple negative breast cancer ,Cancer cell ,Cancer research ,biology.protein ,Adenocarcinoma ,business ,Research Paper - Abstract
// Xuesai Zhang 1 , Qingrou Li 1 , Hui Zhao 1 , Lanping Ma 2 , Tao Meng 2 , Jianchang Qian 1 , Rui Jin 1 , Jingkang Shen 2 and Ker Yu 1 1 Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China 2 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Correspondence to: Ker Yu, email: keryu@fudan.edu.cn Keywords: tissue factor, triple negative breast cancer, pancreatic adenocarcinoma, metastasis, antibody-drug conjugate Received: March 06, 2017 Accepted: June 05, 2017 Published: July 10, 2017 ABSTRACT The pathological presence of tissue factor (TF) in cancer cells promotes tumor-initiated thrombosis and cancer metastasis. We found that TF is aberrantly present in large percentage of aggressive triple negative breast cancer (TNBC) and pancreatic adenocarcinoma (PaC), two most lethal forms of malignancy that urgently need effective treatment. TF expression in TNBC clustered with higher levels of vimentin, basal-type keratins KRT5/14 and caveolin-1 but lower levels of luminal-type biomarkers. We developed a novel and specific anti-TF therapeutic antibody SC1, which displayed an exceedingly high potency against TF extracellular domain (EC 50 : 0.019 nM), TF-positive TNBC- or PaC cells (EC 50 : 2.5 nM), intracellular protease activated receptor 2 (PAR2) signaling (IC 50 : 2-3 nM) and tumor-initiated coagulation (IC 50 : 100 nM) achieving >5000 fold target selectivity. Following a weekly intravenous administration, SC1-MMAE and its humanized hSC1-MMAE inhibited TNBC- and PaC tumor growth achieving MED of 0.3-1 mg/kg and were both well tolerated. Thus, the prevalent TF expression in TNBC and PaC renders these challenging tumors highly susceptible to TF-targeted treatment and may offer new opportunity in cancer patients.
- Published
- 2017
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