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.

中文翻译：

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的发现ñ - （3 - （（1- Isonicotinoylpiperidin -4-基）氧基）-4-甲基苯基）-3-（三氟甲基）苯甲酰胺（CHMFL-KIT-110），为选择性的，有效的，并且可口服类型II C语言-KIT激酶抑制剂在胃肠道间质瘤（GIST）中的应用

c-KIT激酶是胃肠道间质瘤（GIST）的有效药物发现靶标。临床使用的c-KIT激酶抑制剂，即伊马替尼和舒尼替尼，还具有其他重要的靶标，例如ABL或FLT3激酶。在这里，我们报告了我们发现的更具选择性的c-KIT抑制剂化合物13（CHMFL-KIT-110），该化合物完全废除了ABL和FLT3激酶活性。KinomeScan选择性分析（468个激酶）中有13种显示出高选择性（S分数（1）= 0.01）。13展示了对GISTs细胞系GIST-T1和GIST-882（GI ₅₀：分别为0.021和0.043μM）。在细胞环境中，它有效地影响了c-KIT介导的信号通路，并诱导了细胞凋亡以及细胞周期停滞。此外，13个具有可接受的生物利用度（36％），并有效地抑制了GIST-T1细胞接种异种移植模型中的肿瘤生长，而没有明显的毒性。目前有13个正在接受广泛的临床前评估，并且可能是GIST的潜在候选药物。