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Updated: Feb 22, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

Johannes Brägelmann1, Marcel A Dammert1, Felix Dietlein2

  • 1Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.

Cell Reports
|September 21, 2017
PubMed

Insights

BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells exhibit a specific vulnerability to cyclin-dependent kinase 9 inhibition (CDK9i). This targeted therapy induces apoptosis and DNA damage response, offering a potential new treatment avenue for NMC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Kinase inhibitors are crucial for targeted cancer therapy, but druggable oncogenic drivers remain limited.
  • BRD4-NUT fusion proteins drive specific cancers like NUT midline carcinoma (NMC).

Purpose of the Study:

  • To identify specific vulnerabilities in BRD4-NUT-rearranged NMC cells.
  • To investigate the mechanistic basis of targeted therapy response in NMC.

Main Methods:

  • Screening of 1,505 kinase inhibitors against NMC cells.
  • Analysis of cell death, DNA damage markers, protein expression (Myc), and cell cycle.
  • RNA sequencing and ChIP analyses to study transcriptional changes.

Main Results:

  • CDK9 inhibition (CDK9i) specifically kills NMC cells dependent on CDK9 and Cyclin-T1.
  • CDK9i induces apoptosis and DNA damage response.
  • CDK9i perturbs transcriptional elongation in a BRD4-NUT-specific manner, distinct from bromodomain inhibition effects.

Conclusions:

  • NMC cells show a genotype-dependent vulnerability to CDK9i.
  • CDK9i offers a promising, mechanistically understood therapeutic strategy for NMC.
  • Understanding this vulnerability may guide the development of novel targeted therapies for NMC.
Keywords:
CDK9 inhibitorNUT midline carcinomahigh-throughput screentranscriptional elongation

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