Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation

Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 d...

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Published in:Nature chemical biology Vol. 14; no. 2; p. 163
Main Authors: Olson, Calla M, Jiang, Baishan, Erb, Michael A, Liang, Yanke, Doctor, Zainab M, Zhang, Zinan, Zhang, Tinghu, Kwiatkowski, Nicholas, Boukhali, Myriam, Green, Jennifer L, Haas, Wilhelm, Nomanbhoy, Tyzoon, Fischer, Eric S, Young, Richard A, Bradner, James E, Winter, Georg E, Gray, Nathanael S
Format: Journal Article
Language:English
Published: United States Nature Publishing Group 01.02.2018
Subjects:
Apoptosis
Cancer
Cell Line, Tumor
Cell Proliferation
Conjugation
Crystallography, X-Ray
Cyclin-dependent kinase 9
Cyclin-Dependent Kinase 9 - antagonists & inhibitors
Cyclin-Dependent Kinase 9 - chemistry
Cyclin-dependent kinases
Cytotoxicity
Degradation
Elongation
Humans
Inhibitory Concentration 50
Kinases
Ligands
Oxazoles - pharmacology
Peptide Hydrolases - chemistry
Pharmacology
Phosphorylation
Protein Binding
Protein Conformation
Protein Kinase Inhibitors - pharmacology
Proteomics
Thalidomide
Thalidomide - pharmacology
Thiazoles - pharmacology
Transcription elongation
Ubiquitin
Ubiquitin-protein ligase
ISSN:1552-4450, 1552-4469, 1552-4469
Online Access:Get full text
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Summary:Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
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ISSN:1552-4450
1552-4469
1552-4469
DOI:10.1038/nchembio.2538