Pevonedistat hydrochloride is an effective and selective inhibitor of NEDD8-activating enzyme (IC50: 4.7 nM).

Pevonedistat is an effective inhibitor of NAE (half-maximal inhibitory concentration (IC50=0.004 μM), and is selective relative to the closely related enzymes UAE, SAE, UBA6 and ATG7 (IC50=1.5, 8.2, 1.8 and >10 μM, respectively). Pevonedistat (MLN4924) rapidly inhibits cullin 1 neddylation and remarkably suppressed growth and survival as well as migration in a dose-and time-dependent manner in gastric cancer cells, and significantly suppresses migration by transcriptionally activating E-cadherin and repressing MMP-9. Pevonedistat induces CLL cell apoptosis and circumvented stroma-mediated resistance. Pevonedistat promotes induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. Pevonedistat treatment inhibits overall protein turnover in cultured HCT-116 cells. Treatment of HCT-116 cells with Pevonedistat for 24 h causes a dose-dependent decrease of Ubc12-NEDD8 thioester and NEDD8-cullin conjugates (IC50< 0.1 μM) resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2 (also known as NFE2L2), but not non-CRL substrates[1][2][3].

Pevonedistat administered on a BID schedule at 30 and 60 mg/kg inhibits tumor growth (T/C: 0.36 and 0.15, respectively). Pevonedistat (30 or 60 mg/kg, s.c.) causes a dose- and time-dependent enhance the steady-state levels of NRF2 and CDT1 in HCT-116 tumor-bearing mice and reduces NEDD8-cullin levels in normal mouse tissue as illustrated in mouse bone marrow cells [1].

1160295-21-5

C21H26ClN5O4S

479.98

MLN4924 hydrochloride;Pevonedistat hydrochloride

H2O:10 mg/mL (20.83 mM),Need ultrasonic
DMSO:100 mg/mL (208.34 mM),Need ultrasonic
Powder: -20°C for 3 years
In solvent: -80°C for 2 years