2. Academic Validation
  3. Targeted degradation of CDK9 potently disrupts the MYC-regulated network

Targeted degradation of CDK9 potently disrupts the MYC-regulated network

  • Cell Chem Biol. 2025 Apr 17;32(4):542-555.e10. doi: 10.1016/j.chembiol.2025.03.001.
Mohammed A Toure 1,  Keisuke Motoyama 2,  Yichen Xiang 1,  Julie Urgiles 3,  Florian Kabinger 2,  Ann-Sophie Koglin 4,  Ramya S Iyer 4,  Kaitlyn Gagnon 4,  Amruth Kumar 4,  Samuel Ojeda 4,  Drew A Harrison 4,  Matthew G Rees 5,  Jennifer A Roth 5,  Christopher J Ott 6,  Richard Schiavoni 7,  Charles A Whittaker 7,  Stuart S Levine 8,  Forest M White 9,  Eliezer Calo 10,  Andre Richters 2,  Angela N Koehler 11
Affiliations

Affiliations

  • 1 Koch 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.
  • 2 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, 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.
  • 3 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 04142, USA; Harvard-MIT Health Sciences and Technology, Boston, MA 02115, USA.
  • 4 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA 04142, USA.
  • 6 Broad Institute of MIT and Harvard, Cambridge, MA 04142, USA; Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
  • 8 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; MIT BioMicro Center, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 USA.
  • 9 Koch 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.
  • 10 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 11 Koch 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. Electronic address: koehler@mit.edu.
PMID: 40154489 DOI: 10.1016/j.chembiol.2025.03.001
Abstract

CDK9 coordinates signaling events that regulate transcription and is implicated in oncogenic pathways, making it an actionable target for drug development. While numerous CDK9 inhibitors have been developed, success in the clinic has been limited. Targeted degradation offers a promising alternative. A comprehensive evaluation of degradation versus inhibition is needed to assess when degradation might offer superior therapeutic outcomes. We report a selective and potent CDK9 Degrader with rapid kinetics, comparing its downstream effects to those of a conventional inhibitor. We validated that CDK9 inhibition triggers a compensatory feedback mechanism that dampens its anticipated effect on MYC expression and found that this was absent when degraded. Importantly, degradation is more effective at disrupting MYC transcriptional regulation and subsequently destabilizing nucleolar homeostasis, likely by abrogation of both enzymatic and scaffolding functions of CDK9. These findings suggest that CDK9 degradation offers a more robust strategy to overcome limitations associated with its inhibition.

Keywords

CDK9; MYC; PROTAC; cancer therapy; degradation vs. inhibition; targeted degradation; transcription.

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