Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants
Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants
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(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑-2-基)-2-(4的发现
DOI：
10.1016/j.ejmech.2020.112744
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发表时间：
2020-12-01
影响因子：
6.7
通讯作者：
Liu, Jing
中科院分区：
文献类型：
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作者：
Wang, Beilei;Zhang, Wentao;Liu, Jing
由于融合的NTRK基因在多种癌症中的关键致瘤作用，TRK激酶作为药物发现靶点引起了广泛关注。从基于吲唑的支架开始，通过具有闭环策略的II型激酶抑制剂片段杂合设计方法，我们发现了新的有效的II型TRK激酶抑制剂化合物34（IHMT-TRK-284），其对TRKA、B和C的IC 50值分别为10.5 nM、0.7 nM和2.6 nM。此外，当在468种激酶和突变体中测试时，它在激酶组中显示出很大的选择性特征（在1 μ M时S评分（1）= 0.02）。重要的是，34可以克服包括ATP结合口袋中的V573 M和F589 L以及DFG区域中的G667 C/S在内的耐药突变体。在体内，34在不同种属（包括小鼠、大鼠和犬）中表现出良好的PK特征。它还在TRKA/B/C、TRKA突变体和KM-12-LUC细胞介导的小鼠模型中显示出良好的体内抗肿瘤功效。针对临床上重要的TRK突变体的有效活性与34的良好体内PK和功效特性相结合，表明其可能是TRK激酶融合或突变体驱动的癌症的新的潜在治疗候选物。(C)2020 Elsevier Masson SAS。All rights reserved.
Due to the critical tumorigenic role of fused NTRK genes in multiple cancers, TRK kinases have attracted extensive attention as a drug discovery target. Starting from an indazole based scaffold, through the type II kinase inhibitor fragments hybrid design approach with a ring closure strategy, we discovered a novel potent type II TRK kinase inhibitor compound 34 (IHMT-TRK-284), which exhibited IC50 values of 10.5 nM, 0.7 nM and 2.6 nM to TRKA, B, and C respectively. In addition, it displayed great selectivity profile in the kinome when tested among 468 kinases and mutants (S score (1) = 0.02 at 1 mu M). Importantly, 34 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region. In vivo, 34 exhibited good PK profiles in different species including mice, rats, and dogs. It also displayed good in vivo antitumor efficacies in the TRKA/B/C, TRKA mutants, and KM-12-LUC cells mediated mouse models. The potent activity against clinically important TRK mutants combined with the good in vivo PK and efficacy properties of 34 indicated that it might be a new potential therapeutic candidate for TRK kinase fusion or mutants driven cancers. (C) 2020 Elsevier Masson SAS. All rights reserved.