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)

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.

c-KIT激酶的增益功能突变在胃肠道间质瘤（GISTs）的病理发生中扮演着至关重要的角色。尽管伊马替尼作为GISTs的一线治疗药物取得了显著成效，但仍然出现了数十种药物获得的耐药突变，其中c-KIT T670I突变是最为常见的突变之一。尽管存在数种能够克服T670I突变的激酶抑制剂，但它们均无法实现对c-KIT野生型（wt）的选择性抑制，而c-KIT野生型在诸如造血等众多生理功能中也发挥着重要作用。本研究从阿昔替尼出发，通过片段杂交型II类激酶抑制剂的设计方法，成功发现了一种新型抑制剂24，它不仅对c-KIT T670I突变展现出强大的活性，而且对c-KIT野生型的选择性提高了12倍。化合物24对由c-KIT T670I突变驱动的GIST细胞系（GIST-T1/T670I和GIST-5R）表现出良好的抗增殖作用，并在体内药代动力学特性和剂量依赖的抗肿瘤效果方面展现出适宜的特性。本研究为开发一种针对c-KIT突变的选择性抑制剂提供了概念验证，理论上该抑制剂能够提供更优的治疗窗口。