| Description | Pevonedistat hydrochloride is an effective and selective inhibitor of NEDD8-activating enzyme (IC50: 4.7 nM). |
| In vitro | 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]. |
| In vivo | 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]. |
| Target activity | NAE:4.7 nM |
| Synonyms | MLN4924 hydrochloride |
| molecular weight | 479.98 |
| Molecular formula | C21H26ClN5O4S |
| CAS | 1160295-21-5 |
| Storage | store at low temperature | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| Solubility | DMSO: 100 mg/mL (208.34 mM), Sonication is recommended. H2O: 10 mg/mL (20.83 mM), Sonication is recommended. |
| References | 1. Soucy TA, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6. 2. J. Claire Godbersen, e tal. The Nedd8-Activating Enzyme Inhibitor MLN4924 Thwarts Microenvironment-Driven NF-κB Activation and Induces Apoptosis in Chronic Lymphocytic Leukemia B Cells. 3. Lan H, et al. Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells. Sci Rep. 2016 Apr 11;6:24218. |