The ubiquitin-proteasome system (UPS) and ubiquitin-like protein (Ubl) conjugation pathways are integral to cellular protein homeostasis. NEDD8 conjugation is essential for the enzymatic function of cullin-RING ligases (CRLs) a family of ubiquitin ligases (E3s) that target protein substrates for degradation by the proteasome, including several substrates with important roles in cancer growth and survival. To test the therapeutic potential of NEDD8 pathway inhibition, we identified an investigational small molecule inhibitor of the NEDD8 Activating Enzyme (NAE) known as MLN4924. NAE catalyses the formation of a NEDD8-inhibitor adduct with MLN4924 by a mechanism referred to as 'substrate assisted inhibition'. MLN4924 is currently being evaluated in clinical trials for solid and hematological malignancies. The discovery of MLN4924, a first in class inhibitor of NAE, and the mechanism of enzyme inhibition will be presented.

Discovery of the Nedd8 activating enzyme inhibitor MLN4924

247th National Meeting (2014)

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