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  2. 合肥物质科学研究院
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  4. 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

文献类型：期刊论文

作者Liu, Xuesong2,3; Wang, Beilei2,3; Chen, Cheng2,3; Jiang, Zongru2,3; Hu, Chen2,3; Wu, Hong2; Zhang, Yicong2,3; Liu, Xiaochuan2; Wang, Wenliang2,3; Wang, Junjie2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2018-12-05
卷号160页码:61-81
关键词ABL kinase Kinase inhibitor ABL mutant CML
ISSN号0223-5234
DOI10.1016/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.
WOS关键词BCR-ABL ; IMATINIB ; RESISTANCE ; MECHANISMS ; STRATEGIES ; BCR-ABL1 ; TUMORS ; DRUG
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000450383500006
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
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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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.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Anhui, Peoples R China
2.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
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.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China
6.Anhui Med Univ, Affiliated Hosp 1, Dept Hematol, Hefei 230022, 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.

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来源：合肥物质科学研究院

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