Targeted degradation of CDK9 potently disrupts the MYC-regulated network

Mohammed A Toure¹, Keisuke Motoyama², Yichen Xiang¹, Julie Urgiles³, Florian Kabinger², Ann-Sophie Koglin⁴, Ramya S Iyer⁴, Kaitlyn Gagnon⁴, Amruth Kumar⁴, Samuel Ojeda⁴, Drew A Harrison⁴, Matthew G Rees⁵, Jennifer A Roth⁵, Christopher J Ott⁶, Richard Schiavoni⁷, Charles A Whittaker⁷, Stuart S Levine⁸, Forest M White⁹, Eliezer Calo¹⁰, Andre Richters², Angela N Koehler¹¹

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
PMCID: PMC12042413 (available on 2026-04-17)
DOI: 10.1016/j.chembiol.2025.03.001

Targeted degradation of CDK9 potently disrupts the MYC-regulated network

Mohammed A Toure et al. Cell Chem Biol. 2025.

. 2025 Apr 17;32(4):542-555.e10.

doi: 10.1016/j.chembiol.2025.03.001. Epub 2025 Mar 27.

Authors

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
PMCID: PMC12042413 (available on 2026-04-17)
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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Conflict of interest statement

Declaration of interests A.N.K. is a scientific co-founder, scientific advisory board member, and equity holder in Kronos Bio. A.N.K., M.A.T., and K.M. have a patent application related to this work. M.A.T., K.M., and A.R. are current employees of Flagship Pioneering, Daiichi Sankyo, and Plexium, respectively.

Update of

Targeted Degradation of CDK9 Potently Disrupts the MYC Transcriptional Network.
Toure MA, Motoyama K, Xiang Y, Urgiles J, Kabinger F, Koglin AS, Iyer RS, Gagnon K, Kumar A, Ojeda S, Harrison DA, Rees MG, Roth JA, Ott CJ, Schiavoni R, Whittaker CA, Levine SS, White FM, Calo E, Richters A, Koehler AN. Toure MA, et al. bioRxiv [Preprint]. 2024 May 15:2024.05.14.593352. doi: 10.1101/2024.05.14.593352. bioRxiv. 2024. Update in: Cell Chem Biol. 2025 Apr 17;32(4):542-555.e10. doi: 10.1016/j.chembiol.2025.03.001. PMID: 38952800 Free PMC article. Updated. Preprint.

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Targeted degradation of CDK9 potently disrupts the MYC-regulated network

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Targeted degradation of CDK9 potently disrupts the MYC-regulated network

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