Discovery of Potent Inhibitors of Cyclin-Dependent Kinases 7 and 9: Design, Synthesis, Structure-Activity Relationship Analysis and Biological Evaluation
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Date
2022
Authors
Chen, R.
Hassankhani, R.
Long, Y.
Basnet, S.K.C.
Teo, T.
Yang, Y.
Mekonnen, L.
Yu, M.
Wang, S.
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Journal article
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ChemMedChem, 2022; 18(3):e202200582-e202200582
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Abstract
Cyclin-dependent kinases (CDKs) 7 and 9 are deregulated in various types of human cancer and are thus viewed as therapeutic targets. Accordingly, small-molecule inhibitors of both CDKs are highly sought-after. Capitalising on our previous discovery of CDKI-73, a potent CDK9 inhibitor, medicinal chemistry optimisation was pursued. A number of N-pyridinylpyrimidin-2-amines were rationally designed, chemically synthesised and biologically assessed. Among them, N-(6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl)-4-(imidazo[1,2-a]pyrimidin-3-yl)pyrimidin-2-amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti-proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4-11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub-G1 phase and induced apoptosis.
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Data source: Supporting information, https://doi.org/10.1002/cmdc.202200582
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Copyright 2022 Wiley-VCH GmbH
Access Condition Notes: Accepted manuscript available after 1 January 2024