A First-in-class Inhibitor, MLN4924 (pevonedistat), Induces Cell-Cycle Arrest, Senescence, and Apoptosis in Human Renal Cell Carcinoma by Suppressing UBE2M-dependent Neddylation Modification.

MLN4924 is a second-generation inhibitor that targets ubiquitin–proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo.