Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase

doi:10.1021/acs.jmedchem.6b00902

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	Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase
	Li, Binhua 1,2; Wang, Aoli 1,3; Liu, Juan 1; Qi, Ziping 1,2; Liu, Xiaochuan 1; Yu, Kailin 1,3; Wu, Hong 1; Chen, Cheng 1,2; Hu, Chen 1,3; Wang, Wenchao 1,2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2016-09-22
卷号	59 期号:18 页码:8456-8472
DOI	10.1021/acs.jmedchem.6b00902
文献子类	Article
英文摘要	cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI(50) = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.
WOS关键词	GASTROINTESTINAL STROMAL TUMORS ; SECONDARY KIT MUTATIONS ; IMATINIB MESYLATE ; C-KIT ; RESISTANCE ; MECHANISMS ; BINDING ; CELLS ; TRIAL ; GIST
WOS研究方向	Pharmacology & Pharmacy
语种	英语
WOS记录号	WOS:000384035300019
资助机构	Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; 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" ; "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 ; CAS/SAFEA international partnership program for creative research teams ; CAS/SAFEA international partnership program for creative research teams ; CAS/SAFEA international partnership program for creative research teams ; CAS/SAFEA international partnership program for creative research teams ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; 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" ; "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 ; CAS/SAFEA international partnership program for creative research teams ; CAS/SAFEA international partnership program for creative research teams ; CAS/SAFEA international partnership program for creative research teams ; CAS/SAFEA international partnership program for creative research teams
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/24253]
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 Magnet Field 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.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 4.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China 5.Univ Pittsburgh, Dept Radiol, Mol Imaging Lab, Pittsburgh, PA 15219 USA 6.Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15261 USA 7.Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA 8.Hefei Cosource Med Technol Co LTD, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Li, Binhua,Wang, Aoli,Liu, Juan,et al. Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(18):8456-8472.
APA	Li, Binhua.,Wang, Aoli.,Liu, Juan.,Qi, Ziping.,Liu, Xiaochuan.,...&Liu, Qingsong.(2016).Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase.JOURNAL OF MEDICINAL CHEMISTRY,59(18),8456-8472.
MLA	Li, Binhua,et al."Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase".JOURNAL OF MEDICINAL CHEMISTRY 59.18(2016):8456-8472.