Discovery of (E)-N1-(3-Fluorophenyl)-N3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)
Discovery of (E)-N1-(3-Fluorophenyl)-N3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)
复制标题
(E)-N-1-(3-氟苯基)-N-3-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)丙二酰胺(CHMFL-KIT-)的发现
DOI：
10.1021/acs.jmedchem.9b00176
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发表时间：
2019-05-23
影响因子：
7.3
通讯作者：
Liu, Jing
中科院分区：
文献类型：
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作者：
Liu, Xuesong;Wang, Beilei;Liu, Jing
c-KIT激酶的功能获得性突变在胃肠道间质瘤（gist）中起着重要的病理作用。尽管伊马替尼作为gist的一线治疗取得了成功，但仍出现了数十种药物获得性耐药突变，其中c-KIT T670I是最常见的突变之一。虽然有几种激酶抑制剂能够克服T670I突变体，但它们都不能达到对c-KIT野生型（wt）的选择性，而c-KIT野生型在造血等多种生理功能中也起着重要作用。从阿西替尼开始，通过片段杂交II型激酶抑制剂设计方法，我们发现了一种新的抑制剂24，它不仅对c-KIT T670I突变体具有有效的活性，而且对c-KIT wt具有12倍的选择性。化合物24对c-KIT T670I突变体驱动的GIST细胞系（GIST- t1 /T670I和GIST- 5r）具有良好的抗增殖作用，并且具有合适的体内药代动力学特征和剂量依赖性的抗肿瘤功效。本研究为开发c-KIT突变体选择性抑制剂提供了概念证明，理论上可以提供更好的治疗窗口。
Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.