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

Haibin Zhou, Jianfeng Lu, Krishnapriya Chinnaswamy, Jeanne A. Stuckey, Liu Liu, Donna McEachern, Chao-Yie Yang, Denzil Bernard, Hong Shen, Liangyou Rui, Yi Sun and Shaomeng Wang ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22924-4

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