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Discovery and characterization of 2-Anilino-4-(Thiazol-5-yl)Pyrimidine transcriptional CDK inhibitors as anticancer agents

Wang, Shudong; Griffiths, Gary; Midgley, Carol A.; Barnett, Anna L.; Cooper, Michael; Grabarek, Joanna; Ingram, Laura; Jackson, Wayne; Kontopidis, George; McClue, Steven J.; McInnes, Campbell; McLachan, Janice; Meades, Christopher; Mezna, Mokdad; Stuart, Iain; Thomas, Mark P.; Zheleva, Daniella I.; Lane, David P.; Jackson, Robert C.; Glover, David M.; Blake, David G. and Fischer, Peter M. (2010). Discovery and characterization of 2-Anilino-4-(Thiazol-5-yl)Pyrimidine transcriptional CDK inhibitors as anticancer agents. Chemistry and Biology, 17(10) pp. 1111–1121.

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The 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.

Item Type: Journal Article
Copyright Holders: 2010 Elsevier Ltd
ISSN: 1074-5521
Keywords: cyclin-dependent kinases; Cdk7; Cdk9; Cdk inhibitors
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 24321
Depositing User: Carol Midgley
Date Deposited: 02 Nov 2010 09:13
Last Modified: 07 Mar 2014 20:44
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