Discovery of a highly selective KIT kinase primary V559D mutant inhibitor for gastrointestinal stromal tumors (GISTs).
KIT kinase V559D mutation is the most prevalent primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs). Here we reported a highly selective KIT V559D inhibitor CHMFL-KIT-031, which displayed about 10-20 fold selectivity over KIT wt in the biochemical assay (IC50: 28 nM over 168 nM; Kd: 266 nM versus 6640 nM) and in cell (EC50: 176 nM versus 2000 nM for pY703) examination. It also displayed 15∼400-fold selectivity over other primary mutants such as L576P and secondary mutants including T670I, V654A (ATP binding pocket) as well as N822K and D816V (activation loop). In addition, it exhibited a selectivity S score (1) of 0.01 among 468 kinases/mutants in the KINOMEScan™ assay. CHMFL-KIT-031 showed potent inhibitory efficacy for KIT V559D mediated signaling pathways in cell and anti-tumor activity in vivo (Tumor Growth Inhibition: 68.5%). Its superior selectivity would make it a good pharmacological tool for further dissection of KIT V559D mediated pathology in the GISTs.
['Yu|Kailin|K|', 'Liu|Xuesong|X|', 'Jiang|Zongru|Z|', 'Hu|Chen|C|', 'Zou|Fengming|F|', 'Chen|Cheng|C|', 'Ge|Juan|J|', 'Wu|Jiaxin|J|', 'Liu|Xiaochuan|X|', 'Wang|Aoli|A|', 'Wang|Wenliang|W|', 'Wang|Wenchao|W|', 'Qi|Ziping|Z|', 'Wang|Beilei|B|', 'Wang|Li|L|', 'Yan|Hezhong|H|', 'Wang|Jiaoxue|J|', 'Ren|Tao|T|', 'Tang|Jun|J|', 'Liu|Qingsong|Q|', 'Liu|Jing|J|']
KIT GISTs KIT V559D primary mutations secondary mutations