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Targeted degradation of CDK9 potently disrupts the MYC-regulated network

Mohammed A Toure1, Keisuke Motoyama2, Yichen Xiang1

  • 1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 04142, USA.

Cell Chemical Biology
|March 28, 2025
PubMed

Insights

Targeted degradation of Cyclin-dependent kinase 9 (CDK9) is more effective than inhibition for cancer therapy. Degradation overcomes feedback mechanisms that limit CDK9 inhibitor efficacy, particularly for MYC regulation.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • Cyclin-dependent kinase 9 (CDK9) is crucial for transcription and implicated in cancer.
  • Existing CDK9 inhibitors show limited clinical success.
  • Targeted protein degradation is an emerging therapeutic strategy.

Purpose of the Study:

  • To compare the therapeutic potential of CDK9 degradation versus inhibition.
  • To evaluate the impact on MYC transcriptional regulation and nucleolar homeostasis.
  • To identify strategies for overcoming limitations of current CDK9-targeted therapies.

Main Methods:

  • Development of a selective and potent CDK9 degrader.
  • Comparison of downstream effects of CDK9 degradation and inhibition.
  • Analysis of MYC expression and nucleolar homeostasis.
  • Investigation of CDK9's enzymatic and scaffolding functions.

Main Results:

  • CDK9 inhibition triggers a compensatory feedback loop, reducing its effect on MYC.
  • CDK9 degradation effectively disrupts MYC transcriptional regulation.
  • Degradation leads to destabilization of nucleolar homeostasis.
  • The compensatory feedback mechanism is absent with CDK9 degradation.

Conclusions:

  • CDK9 degradation offers a superior strategy compared to inhibition.
  • Degradation overcomes feedback mechanisms limiting inhibitor efficacy.
  • Targeted degradation of CDK9 shows promise for overcoming therapeutic challenges in oncology.
Keywords:
CDK9MYCPROTACcancer therapydegradation vs. inhibitiontargeted degradationtranscription

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