Pevonedistat targeting NEDDylation activating enzyme for human diseases: Underlying mechanisms, clinical studies, and future directions

NEDDylation is a crucial post-translational modification wherein the ubiquitin-related molecule NEDD8 is added to lysine residues in substrate proteins via a stepwise enzymatic cascade with the participation of the NEDDylation activating enzyme (NAE, E1), E2 conjugating enzymes, and E3 ligases. Many significant proteins in the NEDDylation process are highly expressed in several human diseases, and suppression of NEDDylation is an attractive strategy to develop novel therapeutic drugs for these diseases. Although a variety of small-molecule inhibitors targeting NEDDylation have been discovered, pevonedistat (also known as MLN4924) is the only NEDDylation inhibitor to date to enter phase III clinical trials. Moreover, many preclinical studies and over 40 clinical trials have fully investigated the potential therapeutic effects of pevonedistat, which has been proven safe for human diseases. A literature search was conducted in X-mol, Web of Science and PubMed, and the keywords to retrieve the literature were pevonedistat and MLN4924. Stepwise enzymatic cascades involved in the NEDDylation process and specific mechanisms underlying pevonedistat binding to NAE were investigated. Crucially, this review also details the research progress of pevonedistat, including the discovery process and design strategies. Through the inhibition of NEDDylation pathway, pevonedistat can alleviate various human diseases, including cancers, metabolic diseases, viral diseases, neurological disorders, cardiac diseases, and autoimmune diseases. Review offers new perspectives for the future research on pevonedistat. By a systematic understanding of relevant findings, this review highlights the immense potential of pevonedistat for human diseases and facilitates the promotion of targeting NEDDylation as a new and effective therapeutic strategy.