Discovery of (RET)-R-wt and (RET)-R-V804M Inhibitors: From Hit to Lead

作者：Mologni Luca; Via Martina Dalla; Chilin Adriana; Palumbo Manlio; Marzaro Giovanni

来源：ChemMedChem, 2017, 12(16): 1390-1398.

DOI：10.1002/cmdc.201700243

• hit-to-lead
• kinases
• pyridines
• pyrimidines
• RET inhibitors

Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET ((RET)-R-wt) and its mutants (e.g., (RET)-R-V804M) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar (RET)-R-wt/(RET)-R-V804M inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido) pyridin-4''-ylamino] phenyl} urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/(RET)-R-wt/(RET)-R-V804M inhibitor.

• 出版日期2017-8-22