NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways[3]. MLN4924 is a potent and selective inhibitor of NAE with an IC50 value of 0.004 μM[3]. MLN4924 inhibits overall protein turnover in cultured HCT-116 cells. Treatment of HCT-116 cells with 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[3]. MLN4924 rapidly inhibits cullin 1 neddylation and remarkably suppresses 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[4]. 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 tumor-bearing mice, and decreases NEDD8-cullin levels in normal mouse tissue as illustrated in mouse bone marrow cells. MLN4924 administered on a BID schedule at 30 and 60 mg/kg inhibits tumor growth with T/C values of 0.36 and 0.15, respectively[3].
Pevonedistat 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
K562 cells
Proliferation assay
72 h
Antiproliferative activity against human K562 cells after 72 hrs by CellTiter-Glo assay, EC50=0.108 μM
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