ND-646 simultaneously inhibits ACC1 and ACC2, thus preventing ACC2 from compensating for the inhibition of ACC1. ND-646 inhibits the dimerization of the hACC2-BC domain under native conditions. In a cell-free system, ND-646 inhibits the enzymatic activity of hACC1 with an IC50 of 3.5 nM and hACC2 with an IC50 of 4.1 nM[1].
ND-646 细胞实验
Cell Line
Concentration
Treated Time
Description
References
OLN93 cells
5 nM
12 h
ND-646 reduced lipid ROS accumulation in OLN93 cells and protected them from ferroptosis.
Redox Biol. 2024 Feb;69:102982.
A549
500 nM
24 h
ND-646 significantly inhibited the proliferation and viability of A549 cells and induced apoptosis and ER stress.
Nat Med. 2016 Oct;22(10):1108-1119.
H157
500 nM
24 h
ND-646 significantly inhibited the proliferation and viability of H157 cells and induced apoptosis and ER stress.
Nat Med. 2016 Oct;22(10):1108-1119.
melanoma cells
4 nM
48 h
ND-646 significantly induced cell death in melanoma cells treated with either media alone or young fibroblast CM, whereas cell death was significantly decreased in the presence of aged fibroblast CM, suggesting that melanoma cells in aged media do not rely solely on fatty acid synthesis as the source of endogenous lipids.
Cancer Discov. 2020 Sep;10(9):1282-1295.
KKU-055
0, 0.1, 0.5, 1.0 µM
24 h
To evaluate the effects of ND-646 on CCA cell proliferation and migration, results showed that ND-646 inhibited colony formation and cell migration in a dose-dependent manner.
Int J Mol Sci. 2024 Sep 22;25(18):10170.
KKU-213A
0, 0.1, 0.5, 1.0 µM
24 h
To evaluate the effects of ND-646 on CCA cell proliferation and migration, results showed that ND-646 inhibited colony formation and cell migration in a dose-dependent manner.
Int J Mol Sci. 2024 Sep 22;25(18):10170.
MDA-MB-231
10 μM
4 d
To evaluate the inhibitory effects of ND-646 on the growth of MDA-MB-231 cells, the results showed that ND-646 had a marginal inhibitory effect on cell growth.
J Exp Med. 2023 Mar 6;220(3):e20221316.
HeLa
10 μM
4 d
To evaluate the inhibitory effects of ND-646 on the growth of HeLa cells, the results showed that ND-646 had a marginal inhibitory effect on cell growth.
J Exp Med. 2023 Mar 6;220(3):e20221316.
HCT116
10 μM
4 d
To evaluate the inhibitory effects of ND-646 on the growth of HCT116 cells, the results showed that ND-646 had a marginal inhibitory effect on cell growth.
J Exp Med. 2023 Mar 6;220(3):e20221316.
HCT-8
10 μM
4 d
To evaluate the inhibitory effects of ND-646 on the growth of HCT-8 cells, the results showed that ND-646 had a marginal inhibitory effect on cell growth.
J Exp Med. 2023 Mar 6;220(3):e20221316.
ND-646 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Intracerebral hemorrhage model
Intracerebroventricular injection
1 μM,1 μL
0, 2, 4, 6 days
ND-646 significantly reduced OPC cell death in the intracerebral hemorrhage model mice and improved cognitive function.
Redox Biol. 2024 Feb;69:102982.
Mice
Neonatal mice (P7)
Intraperitoneal injection
20 mg/kg
Single injection, 15 minutes exposure
To assess whether ND-646 could attenuate VA-induced β-HB depletion, results showed that ND-646 significantly attenuated the drop in β-HB caused by isoflurane exposure
Elife. 2021 Jul 13;10:e65400
Mice
NSCLC xenograft model
Oral
25 mg/kg, 50 mg/kg, 100 mg/kg
Once or twice daily for 31 days
ND-646 significantly inhibited tumor growth in NSCLC xenograft models and reduced fatty acid synthesis in tumors.
Nat Med. 2016 Oct;22(10):1108-1119.
Balb/c Rag-2/Jak3 double-deficient mice
CCA xenograft model
Intraperitoneal injection
100 mg/kg
5 days/week for 2 weeks
To evaluate the effects of SAHA on CCA growth, results showed that SAHA suppressed CCA growth, as demonstrated by reduced tumor size, volume, and weight.
Int J Mol Sci. 2024 Sep 22;25(18):10170.
Mice
Nude mice xenograft model
Oral
25 mg/kg or 50 mg/kg
Once daily for 21 days
To evaluate the inhibitory effects of ND-646 on tumor growth, the results showed that ND-646 significantly inhibited tumor growth.
J Exp Med. 2023 Mar 6;220(3):e20221316.
ND-646 动物研究
Animal study
To assess the effects of prolonged ND-646 treatment on NSCLC tumor progression and to evaluate the impact of bi-daily administration, athymic nude mice with established A549 subcutaneous tumors received oral treatments of either a control vehicle twice daily (BID), ND-646 at 25 mg/kg once daily (QD), ND-646 at 25 mg/kg BID, or ND-646 at 50 mg/kg QD over a span of 31 days. The 25 mg/kg QD dosage of ND-646 proved ineffective in curbing tumor growth. In contrast, ND-646 at 25 mg/kg BID or 50 mg/kg QD markedly reduced the growth of subcutaneous A549 tumors. Throughout the treatment duration, ND-646 was well-tolerated, with no notable weight loss observed, indicating that the maximum tolerated dose (MTD) was not surpassed. Following the final dose, mice were euthanized after 1 hour, and their tissues were processed for either immunohistochemistry (IHC) or immunoblot analysis. Tumors subjected to all ND-646 dosages exhibited a loss of p-ACC detection at 1 hour, confirming effective tumor infiltration and immediate ACC inhibition by ND-646. Importantly, a significant increase in p-EIF2αS51 expression within tumor extracts was only observed at ND-646 dosages that significantly impeded tumor growth (25 mg/kg BID and 50 mg/kg QD)[1].
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