Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia

doi:10.1016/j.ejmech.2018.10.007

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 (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia
	Liu, Xuesong 4,5; Wang, Beilei 4,5; Chen, Cheng 4,5; Jiang, Zongru 4,5; Hu, Chen 4,5; Wu, Hong 4; Zhang, Yicong 4,5; Liu, Xiaochuan 4; Wang, Wenliang 4,5; Wang, Junjie 4,5
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-12-05
卷号	160 页码:61-81
关键词	ABL kinase Kinase inhibitor ABL mutant CML
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.10.007
通讯作者	Ge, Jian(gejian@ahmu.edu.cn) ; Liu, Qingsong(qsliu97@hmfl.ac.cn) ; Liu, Jing(jingliu@hmfl.ac.cn)
英文摘要	There is still a great demand in the clinic for the drugs which can overcome a variety of imatinib resistant ABL mutants. Starting from a type I inhibitor axitinib, which has been reported to overcome ABL-T3151 mutant induced resistance, through a structure guided drug design approach and binding mode switch strategy, we have discovered a novel type II ABL inhibitor 24 (CHMFL-ABL-121), which significantly improved the inhibitory activity against ABL wt and a broad spectrum of mutants including the most prevalent imatinib-resistant gatekeeper mutant 13151. 24 exhibited IC50 values of 2 nM and 0.2 nM against purified inactive ABL wt and 13151 kinase protein respectively and inhibited the proliferation of the established CML cell lines with GI(50) at single digit nM. In cellular context, 24 strongly affected BCR-ABL mediated signaling pathways and induced apoptosis as well as arrested cell cycle at G0/G1 phase. In the in vivo study, 50 mg/kg/day dosage of 24 displayed TGI of 52% in the TEL-ABLT315I-BaF3 cell inoculated allograft mouse model without obvious toxicity. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81200371] ; National Natural Science Foundation of China[U1432250] ; National Natural Science Foundation of China[81471773] ; National Natural Science Foundation of China[81473088] ; National Natural Science Foundation of China[U1532154] ; National Natural Science Foundation of China[81703559] ; National Natural Science Foundation of China[21708044] ; National Key Research and Development Program of China[2016YFA0400900] ; Major Science and Technology Program of Anhui Province[16030801114] ; Major Science and Technology Program of Anhui Province[17030801025] ; Natural Science Foundation of Anhui Province[1708085MH208] ; Natural Science Foundation of Anhui Province[1808085MH274] ; Natural Science Foundation of Anhui Province[1208085QH154] ; Natural Science Foundation of Anhui Province[1708085MH224] ; Natural Science Foundation of the Anhui Higher Education Institutions of China[KJ2018ZD020] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037]
WOS关键词	BCR-ABL ; IMATINIB ; RESISTANCE ; MECHANISMS ; STRATEGIES ; BCR-ABL1 ; TUMORS ; DRUG
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000450383500006
资助机构	National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; 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内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/34322]
专题	合肥物质科学研究院_中科院强磁场科学中心合肥物质科学研究院_合肥创新院
通讯作者	Ge, Jian; Liu, Qingsong; Liu, Jing
作者单位	1.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China 2.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Anhui, Peoples R China 3.Anhui Med Univ, Affiliated Hosp 1, Dept Hematol, Hefei 230022, Anhui, Peoples R China 4.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China 5.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 6.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Liu, Xuesong,Wang, Beilei,Chen, Cheng,et al. Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,160:61-81.
APA	Liu, Xuesong.,Wang, Beilei.,Chen, Cheng.,Jiang, Zongru.,Hu, Chen.,...&Liu, Jing.(2018).Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,160,61-81.
MLA	Liu, Xuesong,et al."Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 160(2018):61-81.