Discovery of a highly selective KIT kinase primary V559D mutant inhibitor for gastrointestinal stromal tumors (GISTs)

// Kailin Yu 1, 2, 3, * , Xuesong Liu 1, 2, 3, * , Zongru Jiang 1, 2, 3, * , Chen Hu 1, 2, 3, * , Fengming Zou 1, 3, 4, 5, * , Cheng Chen 1, 2, 3 , Juan Ge 4, 5 , Jiaxin Wu 1, 2, 3 , Xiaochuan Liu 1, 3, 4, 5 , Aoli Wang 1, 3 , Wenliang Wang 1, 2, 3 , Wenchao Wang 1, 3, 4, 5 , Ziping Qi 1, 3, 4, 5 , Beilei Wang 1, 2, 3 , Li Wang 1, 2, 3 , Hezhong Yan 6 , Jiaoxue Wang 6 , Tao Ren 3, 4, 5 , Jun Tang 6 , Qingsong Liu 1, 2, 3, 4, 5 and Jing Liu 1, 3, 4, 5 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China 2 University of Science and Technology of China, Hefei, Anhui 230036, P. R. China 3 Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China 4 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China 5 Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China 6 Department of Gastroenterology, The 105th Hospital of People’s Liberation Army, Hefei, Anhui 230031, P. R. China * These authors have contributed equally to this work Correspondence to: Jun Tang, email: tangjun1974@163.com Qingsong Liu, email: qsliu97@hmfl.ac.cn Jing Liu, email: jingliu@hmfl.ac.cn Keywords: KIT; KIT V559D; GISTs; primary mutations; secondary mutations Received: September 04, 2017     Accepted: October 28, 2017     Published: November 15, 2017 ABSTRACT 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 TM 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.