Cayman MLN4924

NEDD8 is an ubiquitin-like protein whose activity is required to activate cullin-RING ubiquitin E₃ ligases (CRLs) responsible for the ubiquitination and proteasome-dependent turnover of certain substrates with roles relevant to cellular processes important for cancer cell survival. Neddylation of CRLs is initiated by NEDD8-activating enzyme (NAE), which has become a novel target in cancer therapeutic research. MLN4924 is an analog of adenosine 5’-monophosphate that selectively inhibits NAE (IC₅₀ = 4.7 nM). At much higher concentrations, MLN4924 inhibits the related enzymes ubiquitin-activating enzyme (UAE) and SUMO-activating enzyme (SAE) with IC₅₀ values of 1.5 and 8.2 μM, respectively. At 0.3 μM, MLN4924 has been shown to disrupt CRL-mediated protein turnover leading to apoptosis in HCT116 cells by deregulating S-phase DNA synthesis. In vivo, 30-60 mg/kg MLN4924 dose-dependently suppresses the growth of human tumor xenografts in mice.

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