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

Author

Listed:
  • Haibin Zhou

    (University of Michigan)

  • Jianfeng Lu

    (University of Michigan)

  • Krishnapriya Chinnaswamy

    (University of Michigan)

  • Jeanne A. Stuckey

    (University of Michigan)

  • Liu Liu

    (University of Michigan)

  • Donna McEachern

    (University of Michigan)

  • Chao-Yie Yang

    (University of Michigan)

  • Denzil Bernard

    (University of Michigan)

  • Hong Shen

    (University of Michigan)

  • Liangyou Rui

    (University of Michigan)

  • Yi Sun

    (Zhejiang University)

  • Shaomeng Wang

    (University of Michigan
    University of Michigan
    University of Michigan)

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.

Suggested Citation

  • Haibin Zhou & Jianfeng Lu & Krishnapriya Chinnaswamy & Jeanne A. Stuckey & Liu Liu & Donna McEachern & Chao-Yie Yang & Denzil Bernard & Hong Shen & Liangyou Rui & Yi Sun & Shaomeng Wang, 2021. "Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22924-4
    DOI: 10.1038/s41467-021-22924-4
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