Discovery of <i>N</i>‑(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c‑KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

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 <b>13</b> (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of <b>13</b> exhibited a high selectivity (S score (1) = 0.01). <b>13</b> 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, <b>13</b> possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. <b>13</b> currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs