molecules of the month

Context. Pevonedistat (Takeda) is a first-in-class intravenous or subcutaneous NEDD8-activating enzyme (NAE) inhibitor being developed for leukemia and advanced solid tumors. NAE is a pivotal regulator of the NEDD8 conjugation pathway which regulates the activity of the Cullin-RING ligases (CRLs), key proteins involved in the ubiquitin-proteasome system (UPS), controlling important physiological processes such as cell-cycle and signal transduction. Neddylation of CRLs is an attractive target pathway as CRLs are often abnormally activated in cancers. Pevonedistat, which was first reported in a 2009 publication, is the most advanced NAE inhibitor in clinical development. The only other NAE inhibitor to ever enter clinical development was Otsuka’s TAS4464, which was put on hold after a Ph. I trial was terminated following observation of…