High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
J Med Chem. 2016 Apr 28;59(8):3964-79. doi: 10.1021/acs.jmedchem.6b00200. Epub 2016 Apr 14.
c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.
c-KIT 激酶是胃肠道间质瘤（GIST）的一个经过验证的药物发现靶点。临床上使用的 c-KIT 激酶抑制剂，如伊马替尼和舒尼替尼，还具有其他重要的靶点，如 ABL 或 FLT3 激酶。在这里，我们报告了我们发现的一种更具选择性的 c-KIT 抑制剂，化合物 13（CHMFL-KIT-110），它完全抑制了 ABL 和 FLT3 激酶的活性。13 的激酶组扫描选择性分析（468 种激酶）显示出高度的选择性（S 评分（1）=0.01）。13 对 GIST 细胞系 GIST-T1 和 GIST-882 表现出很强的抗增殖活性（GI50：分别为 0.021 和 0.043 μM）。在细胞环境中，它有效地影响了 c-KIT 介导的信号通路，并诱导了细胞凋亡和细胞周期停滞。此外，13 具有可接受的生物利用度（36%），并能有效地抑制 GIST-T1 细胞接种的异种移植模型中的肿瘤生长，没有明显的毒性。13 目前正在进行广泛的临床前评估，可能是 GIST 的一种潜在药物候选物。
