Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
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Author(s)
Olson, Calla M
Jiang, Baishan
Erb, Michael A
Liang, Yanke
Doctor, Zainab M
Zhang, Zinan
Zhang, Tinghu
Kwiatkowski, Nicholas
Boukhali, Myriam
Green, Jennifer L
Date Issued
December 2017
Journal
Nature Chemical Biology
Publisher
Nature Publishing Group
Citation
Olson, Calla M et al. “Pharmacological Perturbation of CDK9 Using Selective CDK9 Inhibition or Degradation.” Nature Chemical Biology 14, 2 (December 2017): 163–170
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/NCHEMBIO.2538
