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Updated: Mar 26, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated

Aurélie Mallinger1, Kai Schiemann2, Christian Rink1

  • 1Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.

Journal of Medicinal Chemistry
|January 23, 2016
PubMed

Insights

Researchers discovered a new compound, CCT251921, that effectively inhibits CDK8 (cyclin-dependent kinase 8), a protein linked to colorectal cancer. This orally available drug candidate shows promise for further development in cancer models.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Oncology

Background:

  • The Mediator complex-associated cyclin-dependent kinase CDK8 is implicated in human diseases, notably colorectal cancer, where it acts as a potential oncogene.
  • Targeting CDK8 presents a therapeutic strategy for cancers driven by its aberrant activity.

Purpose of the Study:

  • To discover and develop novel, potent, and orally bioavailable inhibitors of CDK8.
  • To optimize lead compounds for favorable pharmacokinetic and physicochemical properties for preclinical development.

Main Methods:

  • Structure-based drug design was employed to identify a 3,4,5-trisubstituted-2-aminopyridine series of inhibitors.
  • Physicochemical property analyses were used to guide optimization, focusing on reducing metabolic clearance and biliary elimination while maintaining solubility.
  • In vitro biochemical and pharmacokinetic assays were performed to evaluate compound potency and drug-like properties.

Main Results:

  • Compound 109 (CCT251921) was identified as a potent and selective inhibitor of CDK8 with equipotent affinity for CDK19.
  • Structure-based design and iterative optimization led to a compound with reduced in vivo metabolic clearance and minimized transporter-mediated biliary elimination.
  • Compound 109 demonstrated an optimal balance of in vitro biochemical, pharmacokinetic, and physicochemical properties.

Conclusions:

  • Compound 109 (CCT251921) represents a promising drug candidate for targeting CDK8 in cancer therapy.
  • The developed inhibitor is suitable for progression into preclinical animal models of cancer.
  • The study highlights the successful application of structure-based design and property-based optimization in drug discovery.

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