Pevonedistat inhibits the NEDD8-activating enzyme, with key effects on the ubiquitination pathway. Pevonedistat is a small-molecule inhibitor of NAE. NEDD8 is a ubiquitin-like protein that is modified and activated in similar fashion to “ubiquitination” by parallel and sequential enzymatic reactions, with both processes interacting and coordinating inside the cell to modify, shuttle, and degrade proteins through the proteasome. By inhibiting NAE, the normal activation in the ubiquitination process of the key ligase, CRL, is downregulated, interfering with the degradation of cellular targets by the proteasome, with resulting effects on cell cycling, apoptosis, and DNA replication. PPi, pyrophosphate; UAE, ubiquitin activation enzyme; Ub, ubiquitin; UBC12, NEDD8 conjugating enzyme. Professional illustration by Somersault 18:24.