MLN-4924 hydrochloride

Research use only, not for human use.

An analog of adenosine 5’-monophosphate that potently and selectively inhibits NEDD8-activating enzyme (NAE) with IC50 of 4.7 nM.

An analog of adenosine 5’-monophosphate that potently and selectively inhibits NEDD8-activating enzyme (NAE) with IC50 of 4.7 nM; also inhibits the related enzymes ubiquitin-activating enzyme (UAE) and SUMO-activating enzyme (SAE) with IC50 of 1.5 and 8.2 uM, respectively; disrupts CRL-mediated protein turnover leading to apoptosis in HCT116 cells, suppresses the growth of human tumor xenografts in mice (30-60 mg/kg).Blood Cancer Phase 2 Clinical.

Pevonedistat (MLN4924) is a potent 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) treatment inhibits overall protein turnover in cultured HCT-116 cells. Treatment of HCT-116 cells with Pevonedistat (MLN4924) for 24 h results in a dose-dependent decrease of Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, with an 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. 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 (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 (MLN492410, 30 or 60 mg/kg, s.c.) leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumour-bearing mice, and decreases NEDD8-cullin levels in normal mouse tissue as illustrated in mouse bone marrow cells. Pevonedistat (MLN4924) administered on a BID schedule at 30 and 60 mg/kg inhibits tumour growth with T/C values of 0.36 and 0.15, respectively.

Pevonedistat hydrochloride | TAK-924 hydrochloride

Proteasome/Ubiquitin

NEDD8

NEDD8

Cancer

Blood cancer

1160295-21-5

479.9803

C21H26ClN5O4S

>98% (HPLC)

DMSO: ≥ 160 mg/mL

C1CC2=CC=CC=C2C1NC3=C4C=CN(C4=NC=N3)C5CC(C(C5)O)COS(=O)(=O)N.Cl

Sulfamic acid, [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl ester, hydrochloride (1:1)

(-20℃)

With Ice Pack

≥ 2 years