Εμφάνιση απλής εγγραφής

dc.creatorWang, S.en
dc.creatorGriffiths, G.en
dc.creatorMidgley, C. A.en
dc.creatorBarnett, A. L.en
dc.creatorCooper, M.en
dc.creatorGrabarek, J.en
dc.creatorIngram, L.en
dc.creatorJackson, W.en
dc.creatorKontopidis, G.en
dc.creatorMcClue, S. J.en
dc.creatorMcInnes, C.en
dc.creatorMcLachlan, J.en
dc.creatorMeades, C.en
dc.creatorMezna, M.en
dc.creatorStuart, I.en
dc.creatorThomas, M. P.en
dc.creatorZheleva, D. I.en
dc.creatorLane, D. P.en
dc.creatorJackson, R. C.en
dc.creatorGlover, D. M.en
dc.creatorBlake, D. G.en
dc.creatorFischer, P. M.en
dc.date.accessioned2015-11-23T10:54:09Z
dc.date.available2015-11-23T10:54:09Z
dc.date.issued2010
dc.identifier10.1016/j.chembiol.2010.07.016
dc.identifier.issn10745521
dc.identifier.urihttp://hdl.handle.net/11615/34662
dc.description.abstractThe main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins. We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i.e., CDK7 and especially CDK9. The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation. This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups. We describe the characterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells. A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5-[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H- thiazol-2-one, with anticancer activity in animal models. © 2010 Elsevier Ltd All rights reserved.en
dc.source.urihttp://www.scopus.com/inward/record.url?eid=2-s2.0-78049404246&partnerID=40&md5=e88fdc48a146ea711ad620e6b7df4a2a
dc.subjectantineoplastic agenten
dc.subjectcyclin dependent kinaseen
dc.subjectprotein kinase inhibitoren
dc.subjectprotein p53en
dc.subjectpyrimidine derivativeen
dc.subjectanimalen
dc.subjectapoptosisen
dc.subjectarticleen
dc.subjectbinding siteen
dc.subjectchemistryen
dc.subjectcomputer simulationen
dc.subjectdisease modelen
dc.subjectdrug antagonismen
dc.subjectdrug effecten
dc.subjectdrug screeningen
dc.subjectgenetic transcriptionen
dc.subjectgeneticsen
dc.subjecthumanen
dc.subjectleukemiaen
dc.subjectmetabolismen
dc.subjectmouseen
dc.subjecttumor cell lineen
dc.subjectAnimalsen
dc.subjectAntineoplastic Agentsen
dc.subjectBinding Sitesen
dc.subjectCell Line, Tumoren
dc.subjectCyclin-Dependent Kinasesen
dc.subjectDisease Models, Animalen
dc.subjectDrug Evaluation, Preclinicalen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectProtein Kinase Inhibitorsen
dc.subjectPyrimidinesen
dc.subjectTranscription, Geneticen
dc.subjectTumor Suppressor Protein p53en
dc.subjectAnimaliaen
dc.titleDiscovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agentsen
dc.typejournalArticleen


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