From Lead to Drug Candidate:Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine De

• 作 者: Chun-HuiZhang[1]KaiChen[1]YanJiao[1]Lin-LiLi[2]Ya-PingLi[1]Rong-JieZhang[1]Ming-WuZheng[1]LeiZhong[1]Shen-ZhenHuang[1]Chun-LiSong[2]Wan-TingLin[1]JiaoYang[1]RongXiang[3]BingPeng[1]Jun-HongHan[1]Guang-
• 机 构: State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and Collaborative Innovatio
• 出 处: 第九届国际分子模拟与信息技术应用学术会议(ICMS&I2018)
• 发表日期: 2018年期

　　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.