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Related Experiment Video

Updated: Feb 22, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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.

|September 21, 2017

Summary

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.

Keywords:

CDK9 inhibitor NUT midline carcinoma high-throughput screen transcriptional elongation

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Last 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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Published on: October 26, 2015

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

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.