DCN-type NEDD8 E3 ligases: Structure, biological function and small-molecule inhibitor

Defective in cullin neddylation 1-5 (DCN1-5) are critical E3 ligases of the neddylation pathway that participate in post-translational modification by selectively catalyzing cullin neddylation, thus mediating the activation of Cullin-RING Ligases (CRLs), and further modulating the activity of target proteins. Currently, DCN1-5 have been identified to play vital roles in cancer, fibrotic diseases, and several other human diseases. Inhibitors targeting DCN1 with various chemotypes had been developed and evaluted in cancer and many NRF2-related diseases. As described above, this review provides insights into the structure and biological functions of DCN1-5, emphasizes the medicinal chemistry advances in the development of DCN1-5 inhibitors, and discusses these five E3 enzymes as appealing therapeutic targets for the treatment of human diseases.