First-in-class, mechanism-based inhibitor of the NEDD8-activating enzyme (NAE1/UBA3), which initiates the neddylation cascade by activating NEDD8 for transfer to E2 conjugating enzymes (UBE2M, UBE2F) and ultimately to cullins. Neddylation of cullins activates cullin-RING E3 ubiquitin ligases, the largest family of ubiquitin E3 ligases. In SDH-deficient tumor cells, an unbiased genome-wide CRISPR-Cas9 synthetic lethality screen identified UBE2F — the neddylation E2 enzyme for cullin-5 — as a selective vulnerability: UBE2F loss suppressed growth specifically in SDHB-deficient chromaffin cells (Al Khazal et al., iScience 2026, PMID: 42181244). Pevonedistat (MLN4924) inhibits NAE upstream of both UBE2F and UBE2M, blocking the entire cullin neddylation cascade. The mechanistic basis for SDH-selectivity likely involves proteotoxic stress: SDH-deficient cells operating under chronic metabolic stress (TCA truncation, ROS, HIF activation) may be disproportionately dependent on cullin-RING-ligase-mediated protein quality control. Pevonedistat has demonstrated acceptable safety in Phase 1/2 trials in hematologic malignancies (Breakthrough Therapy designation by FDA for AML); investigation in SDH-deficient solid tumors is in the preclinical stage.