High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein–Protein Interaction

Zhou, Haibin; Zhou, Weihua; Zhou, Bing; Liu, Liu; Chern, Ting-Rong; Chinnaswamy, Krishnapriya; Lu, Jianfeng; Bernard, Denzil; Yang, Chao-Yie; Li, Shasha; Wang, Mi; Stuckey, Jeanne; Sun, Yi; Wang, Shaomeng

doi:10.1021/acs.jmedchem.7b01455

High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein–Protein Interaction

Journal Article · Mon Feb 12 23:00:00 EST 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b01455· OSTI ID:1499764

Zhou, Haibin ^[1]; Zhou, Weihua ^[1]; ^[1]; Liu, Liu ^[1]; Chern, Ting-Rong ^[1]; Chinnaswamy, Krishnapriya ^[1]; Lu, Jianfeng ^[1]; Bernard, Denzil ^[1]; Yang, Chao-Yie ^[1]; Li, Shasha ^[1]; Wang, Mi ^[1]; Stuckey, Jeanne ^[1]; Sun, Yi ^[2]; ^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Michigan, Ann Arbor, MI (United States); Zhejiang Univ. School of Medicine, Hangzhou, ZJ (China). Inst. of Translational Medicine

Cullin-RING ligases (CRLs) regulate the turnover of approximately 20% of the proteins in mammalian cells and are emerging therapeutic targets in human diseases. The activation of CRLs requires the neddylation of their cullin subunit, which is controlled by an activation complex consisting of Cullin-RBX1-UBC12-NEDD8-DCN1. In this paper, we describe the design, synthesis, and evaluation of peptidomimetics targeting the DCN1-UBC12 protein–protein interaction. Starting from a 12-residue UBC12 peptide, we have successfully obtained a series of peptidomimetic compounds that bind to DCN1 protein with KD values of <10 nM. Determination of a cocrystal structure of a potent peptidomimetic inhibitor complexed with DCN1 provides the structural basis for their high-affinity interaction. Cellular investigation of one potent DCN1 inhibitor, compound 36 (DI-404), reveals that it effectively and selectively inhibits the neddylation of cullin 3 over other cullin members. Further optimization of DI-404 may yield a new class of therapeutics for the treatment of human diseases in which cullin 3 CRL plays a key role.

View Accepted Manuscript (DOE)

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

Sponsoring Organization:: National Key R&D Program of China; National Cancer Institute (NCI); USDOE Office of Science (SC); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1499764

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 5 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited By (2)

Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes Yu, Qing; Hu, Zhiguo; Shen, Yanwen Neoplasia, Vol. 22, Issue 4 https://doi.org/10.1016/j.neo.2020.02.003	journal	April 2020
Targeting the DCN1–UBC12 protein–protein interaction: novel approaches and future directions Fang, Yuan; Yu, Bin; Liao, Guochao Future Medicinal Chemistry, Vol. 11, Issue 22 https://doi.org/10.4155/fmc-2019-0253	journal	November 2019

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Chemical structure
Hydrophobicity
Inhibitors
Peptides and proteins
Screening assays

High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein–Protein Interaction

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