Activating mutations of REarrange during Transfection (RET) kinase frequently occur in human thyroid and lung cancers. An enormous effort has been devoted to discover potent and selective inhibitors of RET. Selective and potent inhibitors against constitutively active RET mutants are rare to date as identification of selective RET inhibitors is challenging. In a recent effort we identified a novel and specific RET inhibitor of 5-aminopyrazole-4-carboxamide scaffold, which was designed to enhance the metabolic stability of the pyrazolopyrimidine scaffold. In the SAR study described in the current report, we identified the 5-aminopyrazole-4-carboxamide analog 15l, which displays high metabolic stability. Compound 15l is potent against gatekeeper mutant (IC50= 252 nM) of RET as well as against wild-type RET (IC50= 44 nM). This substance effectively suppresses growth of Ba/F3 cells transformed with wild-type RET and its gatekeeper mutant (V804M), and thyroid-cancer derived TT cells while it does not affect parental Ba/F3 cells and Nthy ori-3-1, normal thyroid cells. Also, the results of a global kinase profiling assay on a panel of 369 kinases, show that 15l exclusively inhibits RET. Based on its exceptional kinase selectivity, great potency and metabolic stability, 15l represents a promising lead for the discovery of RET directed therapeutic agent and should be a key tool in studies aimed at understanding RET biology.
Bibliographical noteFunding Information:
This work was supported by Korea Institute of Science and Technology (KIST), and the KU-KIST Graduate School of Converging Science and Technology Program , a grant ( D36403 ) of Korea Basic Science Institute, and Creative Fusion Research Program through the Creative Allied Project of the National Research Council of Science & Technology ( CAP-12-1-KIST ).
© 2016 Elsevier Masson SAS
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry