Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation

  • Nat Chem Biol. 2018 Feb;14(2):163-170. doi: 10.1038/nchembio.2538.
Calla M Olson  1  2 ,  Baishan Jiang  1  2 ,  Michael A Erb  3  4 ,  Yanke Liang  1  2 ,  Zainab M Doctor  1  2 ,  Zinan Zhang  1  2 ,  Tinghu Zhang  1  2 ,  Nicholas Kwiatkowski  1  2 ,  Myriam Boukhali  5 ,  Jennifer L Green  6 ,  Wilhelm Haas  5 ,  Tyzoon Nomanbhoy  6 ,  Eric S Fischer  1  2 ,  Richard A Young  7  8 ,  James E Bradner  3  4  9 ,  Georg E Winter  3  4  10 ,  Nathanael S Gray  1  2
Affiliations
  • 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.
PMID: 29251720 DOI: 10.1038/nchembio.2538
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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