Evidence map›Paper›PMID 40154489›Full record

ArticleCell chemical biology2025

Targeted degradation of CDK9 potently disrupts the MYC-regulated network.

Mohammed A Toure, Keisuke Motoyama, Yichen Xiang, Julie Urgiles, Florian Kabinger, Ann-Sophie Koglin, Ramya S Iyer, Kaitlyn Gagnon, Amruth Kumar, Samuel Ojeda and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed.

  1. Review
  2. Generalizable Strategies for the Synthesis of Cereblon-Recruiting PROTAC Prodrugs.Angewandte Chemie (International ed. in English) · 2026
    Article
  3. Targeting MYC-Driven Cancers: From Oncogenic Addiction to Therapeutic Vulnerability.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026
    Review
  4. Article
  5. Review
  6. Article
  7. Review
  8. Article
  9. Article
  10. Article
  11. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors.

Mohammed A ToureKoch 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.
Keisuke MotoyamaKoch 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.
Yichen XiangKoch 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.
Julie UrgilesKoch 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.
Florian KabingerKoch 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.
Ann-Sophie KoglinMassachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Ramya S IyerMassachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Kaitlyn GagnonMassachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Amruth KumarMassachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Samuel OjedaMassachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Drew A HarrisonMassachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Matthew G ReesBroad Institute of MIT and Harvard, Cambridge, MA 04142, USA.
Jennifer A RothBroad Institute of MIT and Harvard, Cambridge, MA 04142, USA.
Christopher J OttBroad 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.
Richard SchiavoniKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
Charles A WhittakerKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
Stuart S LevineKoch 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.
Forest M WhiteKoch 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.
Eliezer CaloKoch 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.
Andre RichtersKoch 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.
Angela N KoehlerKoch 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.

Funding

VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Jacqueline A. Lees · 1985 to 2026
$93.9M
The MIT Superfund Research Program: A Systems Approach for the Protection of Human Health from Hazardous ChemicalsP42ES027707 · NIEHS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Stuart S Levine · 2017 to 2026
$22.2M
Chemical Approaches to Modulate PAX3-FOXO1 in Fusion-Positive Alveolar RhabdomyosarcomaUM1CA294108 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI ALEX B BURGIN, Alexandra E Gould · 2024 to 2026
$6.9M
Screening for Cys-Reactive Ligands to Target PAX3-FOXO1U54CA231630 · NCI · DUKE UNIVERSITY · PI COUNTER, CHRISTOPHER M, LINARDIC, CORINNE MARY · 2019 to 2023
$6.5M
NCI NIH HHS P30 CA014051NCI NIH HHS U54 CA231630NCI NIH HHS UM1 CA294108NIEHS NIH HHS P42 ES027707
6 · The paper itself

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.

Indexed as

Cyclin-Dependent Kinase 9Protein Kinase InhibitorsProto-Oncogene Proteins c-mycHumansProteolysisCDK9 protein, humanCyclin-Dependent Kinase 9Protein Kinase InhibitorsProto-Oncogene Proteins c-myccancer therapyCDK9degradation vs. inhibitionMYCPROTACtargeted degradationtranscription

Identifiers

PMID40154489
PMCPMC12042413

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.