FromLeadtoDrugCandidateOptimizationof3Phenylethynyl1Hpyrazolo[3,4d]pyrimidin4amineDerivativesasAgentsfortheTreatmentofTripleNegativeBreastCancer.pdf
HereinwereportthesophisticatedprocessofstructuraloptimizationtowardapreviouslydisclosedSrcinhibitor,compound1,whichshowedhighpotencyinthetreatmentoftriplenegativebreastcancer(TNBC)bothinvitroandinvivobuthadconsiderabletoxicity.Aseriesof3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminederivativesweresynthesized.Invitrocell-basedphenotypicscreeningtogetherwithinvivoassaysandstructure-activityrelationship(SAR)studiesfinallyledtothediscoveryofN-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide(13an).13anisamultikinaseinhibitor,whichpotentlyinhibitedSrc(IC50=0.003μM),KDR(IC50=0.032μM),andseveralkinasesinvolvedintheMAPKsignaltransduction.Thiscompoundshowedpotentanti-TNBCactivitiesbothinvitroandinvivo,andgoodpharmacokineticpropertiesandlowtoxicity.Mechanismsofactionofanti-TNBCwerealsoinvestigated.Collectively,thedataobtainedinthisstudyindicatethat13ancouldbeapromisingdrugcandidateforthetreatmentofTNBCandhencemeritsfurtherstudies.
作者：Chun-HuiZhang KaiChen YanJiao Lin-LiLi Ya-PingLi Rong-JieZhang Ming-WuZheng LeiZhong Shen-ZhenHuang Chun-LiSong Wan-TingLin JiaoYang RongXiang BingPeng Jun-HongHan Guang-WenLu Yu-QuanWei Sheng-YongYang
作者单位：StateKeyLaboratoryofBiotherapyandCancerCenter,WestChinaHospital,andCollaborativeInnovationCenterforBiotherapy,SichuanUniversity,Sichuan610041,ChinaKeyLaboratoryofDrugTargetingandDrugDeliverySystemofMinistryofEducation,WestChinaSchoolofPharmacy,SichuanUniversity,Chengdu,Sichuan610041,ChinaDepartmentofClinicalMedicine,SchoolofMedicine,NankaiUniversity,Tianjin300071,China
母体文献：第九届国际分子模拟与信息技术应用学术会议(ICMS&I2018)论文集
会议名称：第九届国际分子模拟与信息技术应用学术会议(ICMS&I2018)
会议时间：2018年5月1日
会议地点：太原
主办单位：中国化学会,中科院,北京创腾科技有限公司
语种：chi
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在线出版日期：2019年6月27日
基金项目：
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