Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation

Mingfeng Yu, Theodosia Teo, Yuchao Yang, Manjun Li, Yi Long, Stephen Philip, Benjamin Noll, Gary K. Heinemann, Sarah Diab, Preethi Eldi, Laychiluh Mekonnen, Abel T. Anshabo, Muhammed H. Rahaman, Robert Milne, John D. Hayball, Shudong Wang

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7 Citations (Scopus)


CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent.

Original languageEnglish
Article number113248
Number of pages22
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 15 Mar 2021
Externally publishedYes


  • CDK8 inhibitor
  • Drug-like properties
  • Pharmacokinetics
  • Structure-activity relationship
  • Toxicity

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