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Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents

Shao, Hao, Foley, David, Huang, Shiliang, Abbas, Abdullahi, Lam, Frankie, Gershkovich, Pavel, Bradshaw, Tracey, Pepper, Chris, Fischer, Peter and Wang, Shudong 2021. Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents. European Journal of Medicinal Chemistry 214 , 113244. 10.1016/j.ejmech.2021.113244

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Abstract

Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report our continued efforts in the optimization of 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors. The most selective compound 30m was > 100-fold selective for CDK9 over CDK1 and CDK2. These compounds showed broad anti-proliferative activities in various solid tumour cell lines and patient-derived chronic lymphocytic leukaemia (CLL) cells. Decreased phosphorylation of the carboxyl terminal domain (CTD) of RNAPII at Ser-2 and down-regulation of anti-apoptotic protein Mcl-1 were confirmed in both the ovarian cancer model A2780 and patient-derived CLL cells.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 3 February 2021
Date of Acceptance: 25 January 2021
Last Modified: 03 Aug 2022 01:18
URI: https://orca.cardiff.ac.uk/id/eprint/138210

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