Research Papers:

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

Kailin Yu, Xuesong Liu, Zongru Jiang, Chen Hu, Fengming Zou, Cheng Chen, Juan Ge, Jiaxin Wu, Xiaochuan Liu, Aoli Wang, Wenliang Wang, Wenchao Wang, Ziping Qi, Beilei Wang, Li Wang, Hezhong Yan, Jiaoxue Wang, Tao Ren, Jun Tang _, Qingsong Liu and Jing Liu

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Oncotarget. 2017; 8:111110-111118. https://doi.org/10.18632/oncotarget.22624

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Kailin Yu1,2,3,*, Xuesong Liu1,2,3,*, Zongru Jiang1,2,3,*, Chen Hu1,2,3,*, Fengming Zou1,3,4,5,*, Cheng Chen1,2,3, Juan Ge4,5, Jiaxin Wu1,2,3, Xiaochuan Liu1,3,4,5, Aoli Wang1,3, Wenliang Wang1,2,3, Wenchao Wang1,3,4,5, Ziping Qi1,3,4,5, Beilei Wang1,2,3, Li Wang1,2,3, Hezhong Yan6, Jiaoxue Wang6, Tao Ren3,4,5, Jun Tang6, Qingsong Liu1,2,3,4,5 and Jing Liu1,3,4,5

1High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China

2University of Science and Technology of China, Hefei, Anhui 230036, P. R. China

3Key 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

4Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China

5Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China

6Department 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: [email protected]

Qingsong Liu, email: [email protected]

Jing Liu, email: [email protected]

Keywords: KIT; KIT V559D; GISTs; primary mutations; secondary mutations

Received: September 04, 2017    Accepted: October 28, 2017    Published: November 15, 2017


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 KINOMEScanTM 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.

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