Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic

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dc.contributor.authorC H Jin-
dc.contributor.authorM Krishnaiah-
dc.contributor.authorD Sreenu-
dc.contributor.authorV B Subrahmanyam-
dc.contributor.authorK S Rao-
dc.contributor.authorH J Lee-
dc.contributor.authorS J Park-
dc.contributor.authorH J Park-
dc.contributor.authorKiho Lee-
dc.contributor.authorY Y Sheen-
dc.contributor.authorD K Kim-
dc.date.accessioned2017-04-19T09:54:00Z-
dc.date.available2017-04-19T09:54:00Z-
dc.date.issued2014-
dc.identifier.issn0022-2623-
dc.identifier.uri10.1021/jm500115wko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/12020-
dc.description.abstractA series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6- methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a] pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.013 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.-
dc.publisherAmer Chem Soc-
dc.titleDiscovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic-
dc.title.alternativeDiscovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic-
dc.typeArticle-
dc.citation.titleJournal of Medicinal Chemistry-
dc.citation.number10-
dc.citation.endPage4238-
dc.citation.startPage4213-
dc.citation.volume57-
dc.contributor.affiliatedAuthorKiho Lee-
dc.contributor.alternativeNameJin-
dc.contributor.alternativeNameKrishnaiah-
dc.contributor.alternativeNameSreenu-
dc.contributor.alternativeNameSubrahmanyam-
dc.contributor.alternativeNameRao-
dc.contributor.alternativeName이화정-
dc.contributor.alternativeName박소정-
dc.contributor.alternativeName박현주-
dc.contributor.alternativeName이기호-
dc.contributor.alternativeNameSheen-
dc.contributor.alternativeName김대기-
dc.identifier.bibliographicCitationJournal of Medicinal Chemistry, vol. 57, no. 10, pp. 4213-4238-
dc.identifier.doi10.1021/jm500115w-
dc.description.journalClassY-
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