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Discovery and Characterization of 2-Anilino-4- (Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents

Wang, Shudong and Griffiths, Gary and Midgley, Carol A. and Barnett, Anna L. and Cooper, Michael and Grabarek, Joanna and Ingram, Laura and Jackson, Wayne and Kontopidis, George and McClue, Steven J. and McInnes, Campbell and McLachlan, Janice and Meades, Christopher and Mezna, Mokdad and Stuart, Iain and Thomas, Mark P. and Zheleva, Daniella I. and Lane, David P. and Jackson, Robert C. and Glover, David M. and 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. ISSN 1074-5521.

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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.

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Glover, David M.0000-0003-0956-0103
Additional Information:© 2010 Elsevier. Under an Elsevier user license. Received 6 March 2010, Revised 15 July 2010, Accepted 20 July 2010, Available online 28 October 2010. Accession Numbers. The coordinates of the X-ray crystal structures of compounds 11 and 14 in complex with CDK2 have been deposited with the PDB ( under accession codes 2XMY and 2XNB.
Issue or Number:10
Record Number:CaltechAUTHORS:20200928-150625316
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Official Citation:Shudong Wang, Gary Griffiths, Carol A. Midgley, Anna L. Barnett, Michael Cooper, Joanna Grabarek, Laura Ingram, Wayne Jackson, George Kontopidis, Steven J. McClue, Campbell McInnes, Janice McLachlan, Christopher Meades, Mokdad Mezna, Iain Stuart, Mark P. Thomas, Daniella I. Zheleva, David P. Lane, Robert C. Jackson, David M. Glover, David G. Blake, Peter M. Fischer, Discovery and Characterization of 2-Anilino-4- (Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents, Chemistry & Biology, Volume 17, Issue 10, 2010, Pages 1111-1121, ISSN 1074-5521,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105605
Deposited By: George Porter
Deposited On:29 Sep 2020 14:21
Last Modified:29 Sep 2020 14:21

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