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

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

doi:10.1038/s41467-021-22924-4

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

Journal Article · Tue May 11 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-22924-4· OSTI ID:1787786

^[1]; Lu, Jianfeng ^[1]; Chinnaswamy, Krishnapriya ^[1]; Stuckey, Jeanne A. ^[1]; Liu, Liu ^[1]; McEachern, Donna ^[1]; ^[1]; ^[1]; ^[1]; ^[1]; ^[2]; Wang, Shaomeng ^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
Zhejiang Univ., Hangzhou (China)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Key Research and Development Program of China; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1787786

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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