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

Shao, Hao, Foley, David W, Huang, Shiliang, Abbas, Abdullahi Y, Lam, Frankie, Gershkovich, Pavel, Bradshaw, Tracey D, Pepper, Chris, Fischer, Peter M 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. a13244 1-15. ISSN 0223-5234

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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
Keywords: Anti-Cancer agents, Apoptosis, CDK9 inhibitor, Chronic lymphocytic leukaemia, Mcl-1, RNA polymerase II
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 19 Mar 2021 08:18
Last Modified: 19 Mar 2021 08:18
URI: http://sro.sussex.ac.uk/id/eprint/97888
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