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Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation

2017; Nature Portfolio; Volume: 14; Issue: 2 Linguagem: Inglês

10.1038/nchembio.2538

1552-4469

Calla M. Olson, Baishan Jiang, Michael A. Erb, Yanke Liang, Zainab M. Doctor, Zinan Zhang, Tinghu Zhang, Nicholas Kwiatkowski, Myriam Boukhali, Jennifer L. Green, Wilhelm Haas, Tyzoon Nomanbhoy, Eric S. Fischer, Richard A. Young, James E. Bradner, Georg Winter, Nathanael S. Gray,

Chromatin Remodeling and Cancer

A selective small-molecule degrader of CDK9 was generated by conjugating an imide to SNS-032, a promiscuous ATP-site-directed CDK binder. The pharmacological consequences of CDK9 degradation versus inhibition were compared. 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.