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
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
复制标题
(E)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-(2-(吡啶-2-基)乙烯基)的发现
DOI：
10.1016/j.ejmech.2018.10.007
复制
发表时间：
2018-12-05
影响因子：
6.7
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Liu, Xuesong;Wang, Beilei;Liu, Jing
临床上对能克服多种耐伊马替尼ABL突变的药物仍有很大的需求。从一种已被报道可以克服ABL-T3151突变诱导耐药性的I型抑制剂Axitinib出发，通过结构导向的药物设计方法和结合模式切换策略，我们发现了一种新型的II型ABL抑制剂24(CHFL-ABL-121)，它显著提高了对ABL wt和包括最流行的伊马替尼抗性网守突变体13151在内的一系列突变体的抑制活性。24对纯化的失活ABLwt和13151蛋白的IC50值分别为2nM和0.2nM，并以1位数nM的GI(50)抑制已建立的慢性粒细胞白血病细胞系的增殖。在细胞方面，24强烈影响bcr-abl介导的信号通路，诱导细胞凋亡，并使细胞周期停滞在G0/G1期。体内实验中，TGI为50 mg/kg/d的TGI为52%，TGI为52%。(C)2018年爱思唯尔·马森SAS。版权所有。
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.