A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation

  • Nat Commun. 2017 Oct 27;8(1):1150. doi: 10.1038/s41467-017-01243-7.
Haibin Zhou  1 ,  Jianfeng Lu  1 ,  Liu Liu  1 ,  Denzil Bernard  1 ,  Chao-Yie Yang  1 ,  Ester Fernandez-Salas  2 ,  Krishnapriya Chinnaswamy  3 ,  Stephanie Layton  3 ,  Jeanne Stuckey  3 ,  Qing Yu  4 ,  Weihua Zhou  5 ,  Zhenqiang Pan  6 ,  Yi Sun  5  4 ,  Shaomeng Wang  7  8  9
Affiliations
  • 1. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, 48109, USA.
  • 2. Department of Pathology, University of Michigan, Ann Arbor, Michigan, 48109, USA.
  • 3. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, 48109, USA.
  • 4. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China.
  • 5. Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, 48109, USA.
  • 6. Department of Oncological Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York, 10029, USA.
  • 7. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, 48109, USA. [email protected].
  • 8. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109, USA. [email protected].
  • 9. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA. [email protected].
PMID: 29074978 DOI: 10.1038/s41467-017-01243-7
Abstract

The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of ~20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the development of DI-591 as a high-affinity, cell-permeable small-molecule inhibitor of the DCN1-UBC12 interaction. DI-591 binds to purified recombinant human DCN1 and DCN2 proteins with K i values of 10-12 nM, and disrupts the DCN1-UBC12 interaction in cells. Treatment with DI-591 selectively converts cellular cullin 3 into an un-neddylated inactive form with no or minimum effect on Other cullin members. Our data firmly establish a previously unrecognized specific role of the DCN1-UBC12 interaction for cellular neddylation of cullin 3. DI-591 is an excellent probe compound to investigate the role of the cullin 3 CRL Ligase in biological processes and human diseases.

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