Open AccessDiscovery of a highly selective KIT kinase primary V559D mutant inhibitor for gastrointestinal stromal tumors (GISTs)
Author(s) -
Kewei Yu,
Xuesong Liu,
Zongru Jiang,
Changwei Hu,
Fengming Zou,
Cheng Chen,
Jun Ge,
Jiaxin Wu,
Xiaochuan Liu,
Aoli Wang,
Wenliang Wang,
Wei Wang,
Qi Zhou,
Beilei Wang,
Li Wang,
Yan Huang,
Jiaoxue Wang,
Tao Ren,
Jun Tang,
Qingsong Liu,
Jing Liu
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.22624
Subject(s) - mutant , cancer research , stromal cell , proto oncogene proteins c kit , kinase , in vivo , cell growth , mutation , ic50 , microbiology and biotechnology , chemistry , biology , in vitro , gene , biochemistry , stem cell factor , genetics , stem cell , haematopoiesis
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 (IC 50 : 28 nM over 168 nM; Kd: 266 nM versus 6640 nM) and in cell (EC 50 : 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.