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 (wtRET) and its mutants (e.g., V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wtRET/V804MRET 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/wtRET/V804MRET inhibitor.

Mologni, L., Dalla Via, M., Chilin, A., Palumbo, M., Marzaro, G. (2017). Discovery of wtRET and V804MRET Inhibitors: From Hit to Lead. CHEMMEDCHEM, 12(16), 1390-1398 [10.1002/cmdc.201700243].

Discovery of wtRET and V804MRET Inhibitors: From Hit to Lead

Mologni, Luca
Primo
;
2017

Abstract

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 (wtRET) and its mutants (e.g., V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wtRET/V804MRET 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/wtRET/V804MRET inhibitor.
Articolo in rivista - Articolo scientifico
hit-to-lead; kinases; pyridines; pyrimidines; RET inhibitors; Aminopyridines; Binding Sites; Cell Line, Tumor; Drug Evaluation, Preclinical; Heterocyclic Compounds; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Molecular Docking Simulation; Mutation; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Proto-Oncogene Proteins c-ret; Urea; Molecular Medicine; Pharmacology, Toxicology and Pharmaceutics (all); Organic Chemistry
English
2017
12
16
1390
1398
none
Mologni, L., Dalla Via, M., Chilin, A., Palumbo, M., Marzaro, G. (2017). Discovery of wtRET and V804MRET Inhibitors: From Hit to Lead. CHEMMEDCHEM, 12(16), 1390-1398 [10.1002/cmdc.201700243].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/213643
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