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

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

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. shaomeng@umich.edu.
  • 8 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109, USA. shaomeng@umich.edu.
  • 9 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA. shaomeng@umich.edu.
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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