The ubiquitin–proteasome system is responsible for the regulated degradation of intracellular proteins with important roles in a broad array of cellular functions. The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies and inflammatory diseases. NEDD8-activating enzyme (NAE) is an essential component in the system that regulates the turnover of a subset of proteins and has recently been proved to be an attractive cellular target for the treatment of cancers and inflammatory disorders. In this project, we discovered candidate compounds as inhibitors of NAE from (i) natural product/natural product-like databases using structure-based molecular docking and (ii) a library of rationally designed iridium(III) and rhodium(III) complexes for the treatment of colorectal cancer and inflammatory bowel disease (IBD). The findings of this study contribute to the development of a new class of NAE inhibitors for the treatment of human cancers and inflammatory diseases. In addition, the discovery of potent inhibitors of NAE provides useful tools for cellular and biological investigations on cellular protein degradation.