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Discovery of Potent Inhibitors of Cyclin-Dependent Kinases 7 and 9: Design, Synthesis, Structure-Activity Relationship Analysis and Biological Evaluation.
Chen, Renjie; Hassankhani, Ramin; Long, Yi; Basnet, Sunita K C; Teo, Theodosia; Yang, Yuchao; Mekonnen, Laychiluh; Yu, Mingfeng; Wang, Shudong.
Affiliation
  • Chen R; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Hassankhani R; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Long Y; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Basnet SKC; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Teo T; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Yang Y; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Mekonnen L; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Yu M; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • Wang S; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
ChemMedChem ; 18(3): e202200582, 2023 02 01.
Article in En | MEDLINE | ID: mdl-36400715
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neoplasms / Antineoplastic Agents Limits: Humans Language: En Journal: ChemMedChem Journal subject: FARMACOLOGIA / QUIMICA Year: 2023 Document type: Article Affiliation country: Australia Country of publication: Germany
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neoplasms / Antineoplastic Agents Limits: Humans Language: En Journal: ChemMedChem Journal subject: FARMACOLOGIA / QUIMICA Year: 2023 Document type: Article Affiliation country: Australia Country of publication: Germany