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.; Wang, Shudong

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.

Citation

Shao, H., Foley, D. W., Huang, S., Abbas, A. Y., Lam, F., Gershkovich, P., …Wang, S. (2021). Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents. European Journal of Medicinal Chemistry, 214, Article 113244. https://doi.org/10.1016/j.ejmech.2021.113244

• Journal Article Type: Article
• Acceptance Date: Jan 25, 2021
• Online Publication Date: Feb 2, 2021
• Publication Date: Mar 15, 2021
• Deposit Date: Feb 17, 2021
• Publicly Available Date: Feb 3, 2022
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Electronic ISSN: 1768-3254
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 214
• Article Number: 113244
• DOI: https://doi.org/10.1016/j.ejmech.2021.113244
• Keywords: RNA polymerase II; CDK9 inhibitor; apoptosis; Mcl-1; chronic lymphocytic leukaemia; anti-cancer agents
• Public URL: https://nottingham-repository.worktribe.com/output/5331556
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S0223523421000933?via%3Dihub