In experiments on cellular models, GI254023X markedly inhibits the baseline shedding of RAGE at a concentration of 25 μM, and this inhibitory effect persists, albeit to a lesser extent, at 1 μM. The compound shows a modest reduction in RAGE shedding at a concentration of 100 nM. Distinguishing between various proteinases in vitro, GI254023X exhibits selectivity, demonstrating an IC50 of 541 nM against ADAM17 and more potent inhibition against ADAM10 (IC50=5.3 nM) and MMP9 (IC50=2.5 nM)[1]. The shedding of CXCL16 is obstructed by inhibitors of ADAM proteases, such as GI254023x. A2780 cells, when treated with the ADAM-10/ADAM-17 inhibitor TAPI-2 along with GI254023x, a selective inhibitor for ADAM-10, reveal a significant difference in the expression levels of ADAM-10 mRNA, being almost 9.8 times higher than that of ADAM-17. Moreover, GI254023x efficiently prevents the shedding of CXCL16 from the cell surface, surpassing the effectiveness of TAPI-2[2]. Utilizing the specific inhibitor for ADAM10 (α-secretase), GI254023X, at a concentration of 5 mM on serum/glucose-depleted slices results in a noticeable rise in PI counts compared to slices treated with DMSO (the carrier)[3].
体外研究
In experiments on cellular models, GI254023X markedly inhibits the baseline shedding of RAGE at a concentration of 25 μM, and this inhibitory effect persists, albeit to a lesser extent, at 1 μM. The compound shows a modest reduction in RAGE shedding at a concentration of 100 nM. Distinguishing between various proteinases in vitro, GI254023X exhibits selectivity, demonstrating an IC50 of 541 nM against ADAM17 and more potent inhibition against ADAM10 (IC50=5.3 nM) and MMP9 (IC50=2.5 nM)[1].
The shedding of CXCL16 is obstructed by inhibitors of ADAM proteases, such as GI254023x. A2780 cells, when treated with the ADAM-10/ADAM-17 inhibitor TAPI-2 along with GI254023x, a selective inhibitor for ADAM-10, reveal a significant difference in the expression levels of ADAM-10 mRNA, being almost 9.8 times higher than that of ADAM-17. Moreover, GI254023x efficiently prevents the shedding of CXCL16 from the cell surface, surpassing the effectiveness of TAPI-2[2].
Utilizing the specific inhibitor for ADAM10 (α-secretase), GI254023X, at a concentration of 5 mM on serum/glucose-depleted slices results in a noticeable rise in PI counts compared to slices treated with DMSO (the carrier)[3].
作用机制
GI254023X has an improved fit to the specificity pocket of ADAM10 as compared to that of ADAM17.
GI254023X 细胞实验
Cell Line
Concentration
Treated Time
Description
References
murine mesothelioma PM27 cells
5 µM
16 h
To evaluate the effect of GI254023X on migration and invasion of PM27 cells. Results showed that GI254023X significantly reduced the migratory and invasive abilities of PM27 cells.
Oncogene. 2019 May;38(18):3521-3534.
murine mesothelioma AB12 cells
5 µM
16 h
To evaluate the effect of GI254023X on migration and invasion of AB12 cells. Results showed that GI254023X significantly reduced the migratory and invasive abilities of AB12 cells.
Oncogene. 2019 May;38(18):3521-3534.
DU145 cells
50 μM
24 h
Inhibited ADAM10 activity, reduced the release of ephrin-A5, thereby suppressing the proliferation, migration, and invasion of prostate cancer cells.
Cell Death Dis. 2022 May 12;13(5):453.
Mouse hippocampal neurons
1 µM
From DIV6 to DIV14
GI254023X treatment restored the loss of mushroom dendritic spines and increased the number of excitatory synapses in R6/2 hippocampal neurons.
Cell Mol Life Sci. 2024 Aug 7;81(1):333.
GI254023X 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
AKT/c-Myc-driven HCC model
Intraperitoneal injection
20 mg/kg
From day 10 to day 24
Evaluate the inhibitory effect of ADAM10 inhibitor GI254023X on tumor progression
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