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  • Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.

Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.

Nature chemical biology (2017-12-19)
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 E Winter, Nathanael S Gray
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
SNS-032, ≥98% (HPLC)
Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho-CTD Ser-5) Antibody, clone 3E8, clone 3E8, from rat
Sigma-Aldrich
NVP-2, ≥98% (HPLC)
Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho CTD Ser-2) Antibody, clone 3E10, clone 3E10, from rat
Sigma-Aldrich
THAL-SNS-032, ≥98% (HPLC)