Yoon, Hojong Shin, Injae Nam, Yunju Kim, Nam Doo Lee, Kyung-Bok Sim, Taebo 2024-01-20T02:31:50Z 2024-01-20T02:31:50Z 2021-09-04 2017-01-05 0223-5234 https://pubs.kist.re.kr/handle/201004/123217 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 IT 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. (C) 2016 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER NEOPLASIA TYPE 2B LUNG ADENOCARCINOMA POTENT INHIBITOR CANCER-THERAPY GENE FUSION ISOXAZOLES MUTATIONS RECEPTOR DISEASE Identification of a novel 5-amino-3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-1H-pyrazole-4-carboxa mide as a specific RET kinase inhibitor Article 10.1016/j.ejmech.2016.10.050 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.125, pp.1145 - 1155 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 125 1145 1155 scie scopus 000390496600092 2-s2.0-84994771986 Chemistry, Medicinal Pharmacology & Pharmacy Article NEOPLASIA TYPE 2B LUNG ADENOCARCINOMA POTENT INHIBITOR CANCER-THERAPY GENE FUSION ISOXAZOLES MUTATIONS RECEPTOR DISEASE RET kinase Metabolic stability Specific inhibitor 5-Aminopyrazole-4-carboxamide