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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Normal human cholangiocytes (NHCs) and polycystic human cholangiocytes (PHCs)
0.05 μM
24 and 48 h
To evaluate the effect of Pevonedistat on cystic cholangiocytes, results showed that Pevonedistat significantly inhibited proliferation and induced apoptosis in cystic cholangiocytes.
United European Gastroenterol J. 2021 Sep;9(7):848-859.
RP-Lung SCLC
1.8 ± 0.21 μM
72 h
To evaluate the inhibitory effect of Pevonedistat on SCLC cell proliferation, the results showed an IC50 of 1.8 ± 0.21 μM
Cancer Res. 2020 Jun 1;80(11):2355-2367.
RP-LvMet SCLC
0.18 ± 0.08 μM
72 h
To evaluate the inhibitory effect of Pevonedistat on SCLC cell proliferation, the results showed an IC50 of 0.18 ± 0.08 μM
Cancer Res. 2020 Jun 1;80(11):2355-2367.
H69 SCLC
8.7 ± 1.1 μM
72 h
To evaluate the inhibitory effect of Pevonedistat on SCLC cell proliferation, the results showed an IC50 of 8.7 ± 1.1 μM
Cancer Res. 2020 Jun 1;80(11):2355-2367.
Human cystic cholangiocytes
0.05 μM
24 and 48 h
To evaluate the effect of Pevonedistat on the proliferation and apoptosis of cystic cholangiocytes, results showed that Pevonedistat significantly inhibited proliferation and induced apoptosis in cystic cholangiocytes.
United European Gastroenterol J. 2021 Sep;9(7):848-859.
FaDu
30-3000 nM
72 h
To evaluate the effect of Pevonedistat on the viability of HNSCC cell lines, results showed that Pevonedistat reduced the viability of HNSCC cells in a dose-dependent manner.
Cell Death Dis. 2022 Apr 15;13(4):350.
FaDu
300 nM
24 h
To evaluate the effect of Pevonedistat on DNA damage, results showed that Pevonedistat significantly increased 8-oxoguanine levels, indicating it induces DNA damage.
Cell Death Dis. 2022 Apr 15;13(4):350.
FaDu
100-1000 nM
24 h
To evaluate the effect of Pevonedistat on colony formation in HNSCC cells, results showed that Pevonedistat significantly decreased the clonogenic potential of HNSCC cells.
Cell Death Dis. 2022 Apr 15;13(4):350.
Cal27 cells
50 nM
24 or 48 h
Inhibited cullin neddylation, increased levels of the CRL4CDT2 substrate p21, and resulted in the accumulation of DNA damage.
Mol Cancer Ther. 2018 Feb;17(2):368-380.
FaDu cells
50 nM
24 or 48 h
Inhibited cullin neddylation, increased levels of the CRL4CDT2 substrate p21, and resulted in the accumulation of DNA damage.
Mol Cancer Ther. 2018 Feb;17(2):368-380.
Cal27
50 nM
24 or 48 h
Inhibition of cullin neddylation, increased levels of CRL4CDT2 substrate p21
Mol Cancer Ther. 2018 Feb;17(2):368-380.
FaDu
50 nM
24 or 48 h
Inhibition of cullin neddylation, increased levels of CRL4CDT2 substrate p21
Mol Cancer Ther. 2018 Feb;17(2):368-380.
RMC2C
0.13 μM
48 h
To evaluate the inhibitory effect of Pevonedistat on RMC2C cells, the results showed that Pevonedistat significantly inhibited cell growth with an IC50 concentration of 0.13 μM.
Clin Transl Med. 2023 May;13(5):e1267.
RMC219
0.26 μM
48 h
To evaluate the inhibitory effect of Pevonedistat on RMC219 cells, the results showed that Pevonedistat significantly inhibited cell growth with an IC50 concentration of 0.26 μM.
Clin Transl Med. 2023 May;13(5):e1267.
Pevonedistat 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Subcutaneous xenograft models
Subcutaneously
50 or 90 mg/kg
Daily treatment continued until the end of the experiment
To evaluate the inhibitory effect of Pevonedistat on SCLC tumors, the results showed that Pevonedistat significantly inhibited tumor growth
Cancer Res. 2020 Jun 1;80(11):2355-2367.
Mice
HNSCC xenograft model
Subcutaneous injection
60 mg/kg
5 times per week for 3 weeks
To evaluate the effect of Pevonedistat in combination with cisplatin on HNSCC tumors, results showed that the combination significantly reduced tumor burden and promoted long-term survival.
Cell Death Dis. 2022 Apr 15;13(4):350.
Nude mice
HNSCC xenograft model
Intraperitoneal injection
20 mg/kg
5 days on/5 days off for 2 cycles
Pevonedistat significantly suppressed Cal27 xenografts and further enhanced tumor growth suppression when combined with ionizing radiation (IR).
Mol Cancer Ther. 2018 Feb;17(2):368-380.
Mice
HNSCC xenograft model
Intraperitoneal injection
20 mg/kg
5 days on/5 days off for 2 cycles
To test the effect of Pevonedistat on HNSCC tumor growth, results showed that Pevonedistat significantly suppressed Cal27 xenografts
Mol Cancer Ther. 2018 Feb;17(2):368-380.
Mice
RMC2X and RMC32X PDX models
Intraperitoneal injection
30 mg/kg
Pevonedistat daily for 5 days with 2 days off, 7 days per cycle; Carboplatin and Paclitaxel once per week, 7 days per cycle.
To evaluate the anti-tumor effect of Pevonedistat in combination with Carboplatin and Paclitaxel on RMC2X and RMC32X PDX models, the results showed that the combination therapy significantly inhibited tumor growth.
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