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

• Published in: Journal of medicinal chemistry Vol. 61; no. 5; pp. 1934 - 1950
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.03.2018; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Chemical structure; Chemistry, Medicinal; Crystallography, X-Ray; Cullin Proteins - metabolism; Humans; Hydrophobicity; Inhibitors; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Life Sciences & Biomedicine; Peptides and proteins; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Peptidomimetics - therapeutic use; Pharmacology & Pharmacy; Protein Binding - drug effects; Proteins - antagonists & inhibitors; Proteins - chemistry; Proteins - metabolism; Science & Technology; Screening assays; Ubiquitin-Conjugating Enzymes - chemistry; Ubiquitin-Conjugating Enzymes - metabolism; CULLIN-RING LIGASES; CONJUGATION; DESIGN; UBIQUITIN-PROTEASOME SYSTEM; PATHWAY; DOCKING; DRUG DISCOVERY; TARGETS; NEDD8; ANTAGONISTS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01455

The 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. Herein, 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 K D 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.