From Lead to Drug Candidate:Optimization of 3-(Phenylethynyl)-1H-pyrazolo”3,4-d”pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer
Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor,compound 1,which showed high potency in the treatment of triple negative breast cancer(TNBC)both in vitro and in vivo but had considerable toxicity.A series of 3-(phenylethynyl)-1H-pyrazolo”3,4-d”pyrimidin-4-amine derivatives were synthesized.In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship(SAR)studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo”3,4-d”pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide(13an).13an is a multikinase inhibitor,which potently inhibited Src(IC50 = 0.003 μM),KDR(IC50 = 0.032 μM),and several kinases involved in the MAPK signal transduction.This compound showed potent anti-TNBC activities both in vitro and in vivo,and good pharmacokinetic properties and low toxicity.Mechanisms of action of anti-TNBC were also investigated.Collectively,the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.
Chun-Hui Zhang Kai Chen Yan Jiao Lin-Li Li Ya-Ping Li Rong-Jie Zhang Ming-Wu Zheng Lei Zhong Shen-Zhen Huang Chun-Li Song Wan-Ting Lin Jiao Yang Rong Xiang Bing Peng Jun-Hong Han Guang-Wen Lu Yu-Quan Wei Sheng-Yong Yang
State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and Collaborative Innovatio Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education,West China School Department of Clinical Medicine,School of Medicine,Nankai University,Tianjin 300071,China
国内会议
第九届国际分子模拟与信息技术应用学术会议(ICMS&I2018)
太原
英文
229-246
2018-05-01（万方平台首次上网日期，不代表论文的发表时间）