Targeted degradation of CDK9 potently disrupts the MYC-regulated network
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.
Authors
- Forest M. White (ORCID: https://orcid.org/0000-0002-1545-1651)
- Ann-Sophie Koglin
- Eliezer Calo (ORCID: https://orcid.org/0000-0002-3006-2742)
- Florian Kabinger (ORCID: https://orcid.org/0000-0002-3053-8253)
- Angela N. Koehler (ORCID: https://orcid.org/0000-0001-6980-5534)
- Stuart S. Levine (ORCID: https://orcid.org/0000-0001-7363-562X)
- Mohammed A. Toure (ORCID: https://orcid.org/0000-0002-2472-0729)
- Charles A. Whittaker (ORCID: https://orcid.org/0000-0002-2400-0094)
- Samuel Ojeda (ORCID: https://orcid.org/0000-0001-7121-539X)
- Kaitlyn Gagnon
- Richard P. Schiavoni (ORCID: https://orcid.org/0009-0009-5720-1202)
- André Richters
- Jennifer A. Roth (ORCID: https://orcid.org/0000-0002-5117-5586)
- Yichen Xiang (ORCID: https://orcid.org/0000-0001-9351-6329)
- Julie Urgiles (ORCID: https://orcid.org/0000-0002-9967-0623)
- Matthew G. Rees (ORCID: https://orcid.org/0000-0002-2987-7581)
- Keisuke Motoyama (ORCID: https://orcid.org/0000-0002-4273-960X)
- Amruth Kumar
- Drew A. Harrison
- Ramya S. Iyer
- Christopher J. Ott
Institutions
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Center for Cancer Research (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Cell chemical biology
- Published
- 2025-03-29
- DOI
- https://doi.org/10.1016/j.chembiol.2025.03.001
- Citations
- 8
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 6.45