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
  • 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. [email protected].
  • 6. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 7. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • # 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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