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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Vydáno v:	Nature chemical biology Ročník 14; číslo 2; s. 163
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Nature Publishing Group 01.02.2018
Témata:	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
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1552-4450 1552-4469 1552-4469
DOI:	10.1038/nchembio.2538