A research team from High Magnetic Field Laboratory of the Chinese Academy of Sciences developed a novel pan-KIT kinase inhibitor (CHMFL-KIT-64) against Broad-Spectrum Mutants of c-KIT Kinase. The study was published in Journal of Medicinal Chemistry.

 Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Imatinib was approved as the first-line treatment for advanced GISTs, but may result in secondary mutations upon chronic treatment. Sunitinib and regorafenib were the second-line and third-line therapies which could overcome some of the drug-resistant mutations, but have limited overall clinical response and exhibit severe side effects.

Therefore, new therapeutics which bear different potency profiles against the broad spectrum of the c-KIT mutants are still in great demand.

Through the type II kinase inhibitor binding element hybrid design approach, the researchers discovered a novel c-KIT kinase inhibitor CHMFL-KIT-64, which is potent against c-KIT wild type (wt) and a broad spectrum of c-KIT primary gain-of-function mutants, secondary mutants and A-loop mutants.

CHMFL-KIT-64 exhibits good anti-proliferative effects against imatinib-sensitive cell line GIST-T1, imatinib-resistant cell lines GIST-5R and GIST-T1-T670I as well as the c-KIT wt patient primary cells which are known to be imatinib-resistant. It displayed good in vivo pharmacokinetic properties in different species such as mice, rats and dogs. It also exhibits good in vivo anti-tumor efficacy in the c-KIT T670I, D820G and Y823D mutant-mediated preclinical mice models of GISTs.

This study may provide a new potential therapeutic candidate for GISTs. 

Anti-tumor efficacy of CHMFL-KIT-64 (compd. 18) in the xenograft mouse models (Image by WANG Beilei)