Description
General description
MLN4924 is a specific small molecule NEDD8-activating enzyme (NAE) inhibitor. Neddylation involves adding Nedd8, an ubiquitin-like molecule, to target proteins. This post-translational protein modification is associated with cancer development. MLN4924 is known to induce dose-dependent anti-proliferation, anti-migration, anti-invasion in ccRCC cells. MLN4924 is a cell-permeable AMP mimetic. The mechanism of action is found to target the NEDD8-activating E1 enzyme NAE nucleotide-binding site and undergoes a NAE-catalyzed covalent NEDD8 adduct formation, the adduct in turn acts as a tight-binding, ATP-competitive NAE inhibitor (IC50 = 4.7 nM), exhibiting much reduced or little potency against UAE/UBA1, UBA6/UBE1L2, SAE, ATG7, adenosine receptors A1/A2A/A2B/A3, or a panel of 12 cellular kinases. Selectively reduces cellular Ubc12-NEDD8, but not Ubc9-SUMO or Ubc10-Ub, thioester formation (ICmax = 90 nM in HCT-116 cultures in 24 h), resulting in cullin-RING ligases substrates elevation. Shown to inhibit the growth of various cancer cells both in cultures (IC50 from 50 nM to 1.03 µM) in vitro and in murine xenograft models (30 to 60 mg/kg via s.c.) in vivo via apoptosis induction.
Application
MLN4924 has been used as a neddylation inhibitor:
to treat cell lines stably expressing a GaLV/MLV chimera construct in order to study its effects on viral transduction and infectivity
to study its effects on the accumulation of LCMT1, suggesting a potential role in regulating LCMT1 stability and degradation in LNCaP cells
to study UBX-390-mediated degradation of androgen receptor (AR) via proteasomal action in a prostate cancer cell line
Biochem/physiol Actions
Cell permeable: yes
Primary Target
NEDD8-Activating Enzyme
Reversible: no
Packaging
Packaged under inert gas
Preparation Note
Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 1 month at -20°C.
Use only fresh DMSO for reconstitution.
Other Notes
Milhollen, M.A., et al. 2010. Blood116, 1515.
Brownell, J.E., et al. 2010. Mol. Cell37, 102.
Soucy, T.A., et al. 2009. Nature458, 73.
Legal Information
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
Disclaimer
Toxicity: Standard Handling (A)
