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Discovery of wt RET and V804M RET Inhibitors: From Hit to Lead
Author(s) -
Mologni Luca,
Dalla Via Martina,
Chilin Adriana,
Palumbo Manlio,
Marzaro Giovanni
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700243
Subject(s) - cancer research , vandetanib , medullary thyroid cancer , kinase , thyroid carcinoma , proto oncogene proteins c ret , multiple endocrine neoplasia type 2 , chemistry , tyrosine kinase , protein kinase domain , medicine , thyroid , microbiology and biotechnology , biology , mutant , mutation , biochemistry , receptor , gene , germline mutation , glial cell line derived neurotrophic factor , neurotrophic factors
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 ( wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub‐micromolar wt RET/ V804M RET 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/ wt RET/ V804M RET inhibitor.