2. Academic Validation
  3. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation

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

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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