Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents
Date
2021
Authors
Shao, H.
Foley, D.W.
Huang, S.
Abbas, A.Y.
Lam, F.
Gershkovich, P.
Bradshaw, T.D.
Pepper, C.
Fischer, P.M.
Wang, S.
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Journal article
Citation
European Journal of Medicinal Chemistry, 2021; 214(113244):1-15
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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
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Data source: Supplementary data, https://doi.org/10.1016/j.ejmech.2021.113244
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Copyright 2021 Elsevier Masson SAS