Yu Kailin, Liu Xuesong, Jiang Zongru, Hu Chen, Zou Fengming, Chen Cheng, Ge Juan, Wu Jiaxin, Liu Xiaochuan, Wang Aoli, Wang Wenliang, Wang Wenchao, Qi Ziping, Wang Beilei, Wang Li, Yan Hezhong, Wang Jiaoxue, Ren Tao, Tang Jun, Liu Qingsong, Liu Jing
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
University of Science and Technology of China, Hefei, Anhui 230036, P. R. China.
Oncotarget. 2017 Nov 15;8(67):111110-111118. doi: 10.18632/oncotarget.22624. eCollection 2017 Dec 19.
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: 28 nM over 168 nM; Kd: 266 nM versus 6640 nM) and in cell (EC: 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 (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.
KIT激酶V559D突变是胃肠道间质瘤（GISTs）中最常见的原发性功能获得性突变。在此我们报道了一种高选择性的KIT V559D抑制剂CHMFL-KIT-031，在生化分析中（IC：28 nM对比168 nM；Kd：266 nM对比6640 nM）以及细胞检测中（pY703的EC：176 nM对比2000 nM），它对野生型KIT的选择性约为10 - 20倍。它对其他原发性突变体如L576P以及继发性突变体包括T670I、V654A（ATP结合口袋）以及N822K和D816V（激活环）也表现出了15至400倍的选择性。此外，在KINOMEScan分析中，它在468种激酶/突变体中的选择性S评分(1)为0.01。CHMFL-KIT-031在细胞中对KIT V559D介导的信号通路显示出强效抑制效力以及抗肿瘤活性（肿瘤生长抑制率：68.5%）。其卓越的选择性使其成为进一步剖析GISTs中KIT V559D介导的病理学的良好药理学工具。
