A novel series of N-(pyridin-2-yl)-4-(thiazol-5-yl)pyrimidin-2-amines as highly potent CDK4/6 inhibitors

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dc.contributor.authorTadesse, S.
dc.contributor.authorZhu, G.
dc.contributor.authorMekonnen, L.B.
dc.contributor.authorLenjisa, J.L.
dc.contributor.authorYu, M.
dc.contributor.authorBrown, M.P.
dc.contributor.authorWang, S.
dc.date.issued2017
dc.description.abstractInhibitors of CDK4/6 have emerged as a powerful class of therapeutics for treatment of several malignancies. We herein describe the identification of a new series of molecules that demonstrated excellent selectivity for CDK4/6 over CDKs1, 7 and 9.Medicinal chemistry optimization led to the discovery of 58 and 69 that inhibited CDK4 and CDK4/6, respectively, with high potency and selectivity, and 58 and 69 exhibited potent antiproliferative activities in a panel of human cancer cell lines including leukemia, and cancers of the breast, colon, ovary, pancreas and prostate.Compounds 58 and 69 caused remarkable growth inhibition of melanoma cells, particularly the cells harboring multiple BRAF and NRAS mutations, via a CDK4/6-targeted mechanism of action. [Formula: see text].
dc.description.statementofresponsibilitySolomon Tadesse, Ge Zhu, Laychiluh B Mekonnen, Jimma L Lenjisa, Mingfeng Yu, Michael P Brown, Shudong Wang
dc.identifier.citationFuture Medicinal Chemistry, 2017; 9(13):1495-1506
dc.identifier.doi10.4155/fmc-2017-0076
dc.identifier.issn1756-8919
dc.identifier.issn1756-8927
dc.identifier.orcidBrown, M.P. [0000-0002-5796-1932] [0000-0002-6678-1407]
dc.identifier.urihttp://hdl.handle.net/2440/127114
dc.language.isoen
dc.publisherFuture Science
dc.rights© 2017 Future Science Ltd.
dc.source.urihttps://doi.org/10.4155/fmc-2017-0076
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectAmines
dc.subjectPyridines
dc.subjectPyrimidines
dc.subjectThiazoles
dc.subjectGTP Phosphohydrolases
dc.subjectProto-Oncogene Proteins B-raf
dc.subjectRetinoblastoma Protein
dc.subjectMembrane Proteins
dc.subjectProtein Kinase Inhibitors
dc.subjectCell Proliferation
dc.subjectBinding Sites
dc.subjectProtein Structure, Tertiary
dc.subjectProtein Binding
dc.subjectStructure-Activity Relationship
dc.subjectPhosphorylation
dc.subjectCyclin-Dependent Kinase 4
dc.subjectCyclin-Dependent Kinase 6
dc.subjectG1 Phase Cell Cycle Checkpoints
dc.titleA novel series of N-(pyridin-2-yl)-4-(thiazol-5-yl)pyrimidin-2-amines as highly potent CDK4/6 inhibitors
dc.typeJournal article
pubs.publication-statusPublished

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