2. Academic Validation
  3. Discovery of a highly selective KIT kinase primary V559D mutant inhibitor for gastrointestinal stromal tumors (GISTs)

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

  • Oncotarget. 2017 Nov 15;8(67):111110-111118. doi: 10.18632/oncotarget.22624.
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,  Jing Liu 1 3 4 5
Affiliations

Affiliations

  • 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.
PMID: 29340041 DOI: 10.18632/oncotarget.22624
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 (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.

Keywords

GISTs; KIT; KIT V559D; primary mutations; secondary mutations.

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