2. Academic Validation
  3. Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation

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

  • Eur J Med Chem. 2021 Mar 15;214:113248. doi: 10.1016/j.ejmech.2021.113248.
Mingfeng Yu 1,  Theodosia Teo 1,  Yuchao Yang 1,  Manjun Li 1,  Yi Long 1,  Stephen Philip 1,  Benjamin Noll 1,  Gary K Heinemann 1,  Sarah Diab 1,  Preethi Eldi 2,  Laychiluh Mekonnen 1,  Abel T Anshabo 1,  Muhammed H Rahaman 1,  Robert Milne 1,  John D Hayball 2,  Shudong Wang 3
Affiliations

Affiliations

  • 1 Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
  • 2 Experimental Therapeutics, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
  • 3 Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia. Electronic address: [email protected].
PMID: 33571827 DOI: 10.1016/j.ejmech.2021.113248
Abstract

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.

Keywords

CDK8 inhibitor; Drug-like properties; Pharmacokinetics; Structure-activity relationship; Toxicity.

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