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Nat Chem Biol. 2018 Feb;14(2):163-170. doi: 10.1038/nchembio.2538. Epub 2017 Dec 18.

Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
5
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts, USA.
6
ActivX Biosciences, La Jolla, California, USA.
7
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
8
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
9
Novartis Institutes for Biomedical Sciences (NIBR), Cambridge, Massachusetts, USA.
10
Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

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.

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