Pharmaceutical Inhibition of Neddylation as Promising Treatments for Various Cancers
Background: Neddylation is an important post-translational modification of proteins, in
which a NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is covalently
introduced onto the substrate proteins to regulate their functions and homeostasis. As neddylation is
frequently up-regulated in various cancers, its interference was proposed as a promising therapy of
Objective: The recent advances in developing neddylation interfering agents were summarized to provide
an overview of current achievements and perspectives for future development.
Methods: Reports on neddylation interfering agents were acquired from Pubmed as well as the EPO
and clinicaltrials.gov websites, which were subsequently analyzed and summarized according to targets,
chemical structures and biological activities.
Results: Neddylation as a sophisticated procedure comprises proteolytic processing of NEDD8 precursor,
deploying conjugating enzymes E1 (NAE), E2 (UBE2M and UBE2F) and various E3, as well as
translocating NEDD8 along these conjugating enzymes sequentially and finally to substrate proteins.
Among these nodes, NAE, UBE2M and the interaction between UBE2M-DCN1 have been targeted by
small molecules, metal complexes, peptides and RNAi. A NAE inhibitor pevonedistat (MLN4924) is
currently under evaluation in clinical trials for the treatment of various cancers.
Conclusion: With multiple inhibitory approaches of neddylation being introduced, the development of
neddylation interference as a novel cancer therapy is significantly boosted recently, although its efficacy
and the best way to achieve that are still to be demonstrated in clinical trials.Journal Title:
Current Topics in Medicinal Chemistry