Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding

doi:10.1021/acs.jmedchem.6b01290

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 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding
	Wang, Qiang 1,2; Liu, Feiyang 1,3; Wang, Beilei 1,3; Zou, Fengming 1,2; Qi, Ziping 1,2; Chen, Cheng 1,3; Yu, Kailin 1,3; Hu, Chen 1,3; Qi, Shuang 1,2; Wang, Wenchao 1,2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017-01-12
卷号	60 期号:1 页码:273-289
DOI	10.1021/acs.jmedchem.6b01290
文献子类	Article
英文摘要	The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound. 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC50: 46 nM) and c-KIT kinase (IC50: 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 mu M among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors discovery.
WOS关键词	STRUCTURAL MECHANISM ; TYROSINE KINASE ; BCR-ABL ; RECEPTOR ; MODE ; MET
WOS研究方向	Pharmacology & Pharmacy
语种	英语
WOS记录号	WOS:000392035100018
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) ; 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) ; 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 ; 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 ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of 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 Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; 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) ; 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) ; 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 ; 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 ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of 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 Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973)
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/32787]
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.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 4.Hefei Cosource Med Technol Co Ltd, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China 5.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Wang, Qiang,Liu, Feiyang,Wang, Beilei,et al. Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(1):273-289.
APA	Wang, Qiang.,Liu, Feiyang.,Wang, Beilei.,Zou, Fengming.,Qi, Ziping.,...&Liu, Jing.(2017).Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding.JOURNAL OF MEDICINAL CHEMISTRY,60(1),273-289.
MLA	Wang, Qiang,et al."Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding".JOURNAL OF MEDICINAL CHEMISTRY 60.1(2017):273-289.