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Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents
journal contribution
posted on 2023-06-09, 23:22 authored by Hao Shao, David W Foley, Shiliang Huang, Abdullahi Y Abbas, Frankie Lam, Pavel Gershkovich, Tracey D Bradshaw, Christopher PepperChristopher Pepper, Peter M Fischer, Shudong WangCyclin-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.
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Publication status
- Published
Journal
European Journal of Medicinal ChemistryISSN
0223-5234Publisher
ElsevierExternal DOI
Volume
214Page range
1-15Article number
a13244Event location
FranceDepartment affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2021-03-19Usage metrics
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