Discovery of N-(34(1-lsonicotinoylpiperidin-4-yl)oxy)-4methylpheny1)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

doi:10.1021/acs.jmedchem.6b00200

CORC > 合肥物质科学研究院 > 中国科学院合肥物质科学研究院 > 中科院强磁场科学中心

	Discovery of N-(34(1-lsonicotinoylpiperidin-4-yl)oxy)-4methylpheny1)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)
	Wang, Qang 1,2,3; Liu, Feiyang 1,4; Wang, Beilei 1,2,3; Zou, Fengming 1,2,3; Chen, Cheng 1,2,3; Liu, Xiaochuan 1,5; Wang, Aoli 1,4; Qi, Shuang 1,2,3; Wang, Wenchao 1,2,3; Qi, Ziping 1,2,3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2016-04-28
卷号	59 期号:8 页码:3964-3979
DOI	10.1021/acs.jmedchem.6b00200
文献子类	Article
英文摘要	c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 mu M, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.
WOS关键词	RECEPTOR TYROSINE KINASE ; IMATINIB MESYLATE ; MUTATIONS ; CARDIOTOXICITY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
WOS记录号	WOS:000375519900026
资助机构	National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; National NSFC(U1432250) ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA ; CAS/SAFEA
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/22375]
专题	合肥物质科学研究院_中科院强磁场科学中心
作者单位	1.Chinese Acad Sci, High Field Magnet Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China 2.CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China 3.Chinese Acad Sci, Hefei Inst Phys Sci, CAS Hefei Inst Technol Innovat, Ctr Precis Med, Hefei 230088, Anhui, Peoples R China 4.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 5.Univ Sci & Technol China, Dept Chem, Hefei 230036, Anhui, Peoples R China 6.Hefei Cosource Med Technol Co LTD, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China 7.Changzheng Hosp Joint Ctr Translat Med, Shanghai Changzheng Hosp, Inst Hlth Sci, Inst Translat Med CAS SMMUS,SIBS Inst Hlth Sci, Shanghai 200031, Peoples R China 8.Shanghai Jiao Tong Univ, Chinese Acad Sci, SIBS, Inst Hlth Sci,Key Lab Stem Cell Biol, Shanghai 200031, Peoples R China 9.Collaborat Innovat Ctr Syst Biomed, Shanghai 200025, Peoples R China
推荐引用方式 GB/T 7714	Wang, Qang,Liu, Feiyang,Wang, Beilei,et al. Discovery of N-(34(1-lsonicotinoylpiperidin-4-yl)oxy)-4methylpheny1)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(8):3964-3979.
APA	Wang, Qang.,Liu, Feiyang.,Wang, Beilei.,Zou, Fengming.,Chen, Cheng.,...&Liu, Qingsong.(2016).Discovery of N-(34(1-lsonicotinoylpiperidin-4-yl)oxy)-4methylpheny1)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs).JOURNAL OF MEDICINAL CHEMISTRY,59(8),3964-3979.
MLA	Wang, Qang,et al."Discovery of N-(34(1-lsonicotinoylpiperidin-4-yl)oxy)-4methylpheny1)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)".JOURNAL OF MEDICINAL CHEMISTRY 59.8(2016):3964-3979.