A review on cullin neddylation and strategies to identify its inhibitors for cancer therapy.

The cullin-RING E3 ligases (CRLs) are the biggest components of the E3 ubiquitin ligase protein family, and they represent an essential role in various diseases that occur because of abnormal activation, particularly in tumors development. Regulation of CRLs needs neddylation, a post-translational modification involving an enzymatic cascade that transfers small, ubiquitin-like NEDD8 protein to CRLs. Many previous studies have confirmed neddylation as an enticing target for anticancer drug discoveries, and few recent studies have also found a significant increase in advancement in protein neddylation, including preclinical and clinical target validation to discover the neddylation inhibitor compound. In the present review, we first presented briefly the essence of CRLs' neddylation and its control, systematic analysis of CRLs, followed by the description of a few recorded chemical inhibitors of CRLs neddylation enzymes with recent examples of preclinical and clinical targets. We have also listed various structure-based pointing of protein-protein dealings in the CRLs' neddylation reaction, and last, the methods available to discover new inhibitors of neddylation are elaborated. This review will offer a concentrated, up-to-date, and detailed description of the discovery of neddylation inhibitors. © King Abdulaziz City for Science and Technology 2022.