Related Experiment Video

Updated: Jun 14, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

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

Published on: October 26, 2015

Design, synthesis and biological evaluation of novel CDK8/BRD4 dual inhibitors

Guoao Liang1, Xiaochu Zhang1, Jiayi Zhu1

  • 1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.

Bioorganic & Medicinal Chemistry Letters
|June 12, 2026
PubMed

Insights

Novel dual inhibitors targeting CDK8 and BRD4 show promise for colorectal cancer treatment. Compound 8d effectively suppressed cancer cell growth, offering a new therapeutic strategy.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Biology

Background:

  • Cyclin-dependent kinase 8 (CDK8) is a therapeutic target in colorectal cancer.
  • CDK8 inhibition alone activates compensatory BRD4 signaling, limiting efficacy.
  • Simultaneous CDK8 and BRD4 inhibition shows potential for colorectal cancer treatment.

Purpose of the Study:

  • To design and synthesize novel small-molecule dual inhibitors of CDK8 and BRD4.
  • To evaluate the efficacy of these dual inhibitors against colorectal cancer cells.
  • To provide insights for developing improved CDK8/BRD4 inhibitors.

Main Methods:

  • Fragment merging strategy for inhibitor design.
  • Synthesis of 12 novel small-molecule dual inhibitors.
  • In vitro enzyme inhibition assays for CDK8 and BRD4.
  • Cell proliferation assays using colorectal cancer cell lines.
  • Molecular docking analysis to determine binding modes.

Main Results:

  • Compound 8d demonstrated potent inhibition of both CDK8 (IC50 = 5.44 μM) and BRD4 (IC50 = 4.03 μM).
  • Compound 8d exhibited significant anti-proliferative activity in HCT116 colorectal cancer cells (IC50 = 12.41 μM).
  • Molecular docking provided insights into the binding interactions of compound 8d with CDK8 and BRD4.

Conclusions:

  • The developed CDK8/BRD4 dual inhibitors represent a promising new class of anti-cancer agents.
  • Compound 8d is a lead candidate for further development in colorectal cancer therapy.
  • This study provides a foundation for the rational design of future dual-target inhibitors.
Keywords:
BRD4CDK8Colorectal CancerDual inhibitorNovel

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