Details

Autor(en) / Beteiligte

• 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

Titel

Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation

Ist Teil von

• Nature chemical biology, 2018-02, Vol.14 (2), p.163-170

Ort / Verlag

United States

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.