2. Academic Validation
  3. Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

  • Nat Commun. 2021 May 11;12(1):2621. doi: 10.1038/s41467-021-22924-4.
Haibin Zhou  # 1,  Jianfeng Lu  # 1,  Krishnapriya Chinnaswamy 2,  Jeanne A Stuckey 2,  Liu Liu 1,  Donna McEachern 1,  Chao-Yie Yang 1,  Denzil Bernard 1,  Hong Shen 3,  Liangyou Rui 3,  Yi Sun 4,  Shaomeng Wang 5 6 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 2 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 4 Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 5 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
  • 6 Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
  • 7 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. shaomeng@umich.edu.
  • # Contributed equally.
PMID: 33976147 DOI: 10.1038/s41467-021-22924-4
Abstract

Cullin-RING E3 Ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.

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