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 repressio...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.展开更多
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 investiga...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.展开更多
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 ef...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.展开更多
基金supported financially by the National Science & Technology Major Project ‘Key New Drug Creation and Manufacturing Program’ of China(Grant No.2014ZX09507002)the National Marine ‘863’ Project(No.2013AA092902)
文摘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.
基金financial support from the National Natural Science Foundation of China(Grants No.81661148046 and81773762,China)the "Personalized Medicines-Molecular Signature-based Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(Grants No.XDA12020317,China)+1 种基金the program for Innovative Research Team of the Ministry of Education(China)the program for Liaoning Innovative Research Team at Shenyang Pharmaceutical University(China)
文摘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.
基金This research has been financially supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDA12020323)the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”of China(Grant No.2018ZX09711002-004-009)+3 种基金the Strategic Priority Research Program of Chinese Academy of Sciences(No.SIMM010203)Institutes for Drug Discovery and Development,Chinese Academy of Sciences(No.CASIMM0120215009)National Natural Science Foundation of China(No.U1703235)Shanghai Science and Technology Development Funds(18431907100,China).
文摘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.