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Updated: Nov 17, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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

Mingfeng Yu1, Theodosia Teo1, Yuchao Yang1

  • 1Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.

European Journal of Medicinal Chemistry
|February 11, 2021
PubMed

Insights

Researchers discovered a new pyridine-derived compound, 38 (AU1-100), that potently inhibits CDK8. This novel CDK8 inhibitor shows promise as an oral anti-cancer agent, effectively reducing cancer cell proliferation without systemic toxicity in preclinical studies.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cyclin-dependent kinase 8 (CDK8) is a key regulator of transcription involved in various cancers.
  • CDK8 deregulation is implicated in human cancers and suppresses anti-cancer immune responses.
  • Targeting CDK8 represents a promising strategy for novel cancer drug development.

Purpose of the Study:

  • To discover and optimize novel pyridine-derived inhibitors of CDK8.
  • To evaluate the efficacy and safety of a lead compound, 38 (AU1-100), as a potential anti-cancer therapeutic.

Main Methods:

  • Medicinal chemistry optimization of pyridine derivatives to identify potent CDK8 inhibitors.
  • In vitro assessment of compound 38's effect on MV4-11 acute myeloid leukemia cell proliferation.
  • In vivo evaluation of compound 38's systemic toxicity in mice.

Main Results:

  • Discovery of a series of novel pyridine-derived CDK8 inhibitors.
  • Identification of compound 38 (AU1-100) as a potent CDK8 inhibitor with oral bioavailability.
  • Compound 38 demonstrated efficacy in inhibiting proliferation of MV4-11 cells by dampening cellular CDK8 activity.
  • No systemic toxicity was observed in mice treated with compound 38.

Conclusions:

  • Compound 38 (AU1-100) is a potent and orally bioavailable CDK8 inhibitor.
  • 38 exhibits anti-cancer activity against acute myeloid leukemia cells.
  • The preclinical data support further investigation of compound 38 as a potential anti-cancer agent.
Keywords:
CDK8 inhibitorDrug-like propertiesPharmacokineticsStructure-activity relationshipToxicity

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