GI254023X

GI254023X
Cat. No. : CS-7675 CAS No. : 260264-93-5
M. Wt. : 391.50
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5mg In-stock $185.0
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  • Data Sheet

  • Introduction

  • SDS

  • COA & Spectra

Name: GI254023X; GI4023; SRI028594
Cat. No. : CS-7675
CAS No. : 260264-93-5
Formula: C21H33N3O4
M. Wt. : 391.50
Solubility: DMSO

Activity:

GI254023X is a potent MMP9 and ADAM10 inhibitor with IC50 of 2.5 and 5.3 nM, respectively. IC50 & Target: IC50: 2.5 nM (MMP9), 5.3 nM (ADAM10)[1] In Vitro: In cellular assay 25 µM and even a concentration of 1 µM GI254023X strongly reduced constitutive RAGE shedding; also PACAP-induced shedding of RAGE is significantly reduced. At a concentration of 100 nM, a slight inhibition of RAGE shedding is still observed. In in vitro assays with recombinant proteinases, GI254023X discriminates between ADAM17 (IC50 = 541 nM) and ADAM10 (IC50 = 5.3 nM)/MMP9 (IC50 = 2.5 nM)[1]. CXCL16 shedding is inhibited by ADAM protease inhibitors (e.g GI254023x) .A2780 cells are incubated with the ADAM-10/ADAM-17 inhibitor TAPI-2, as well as the ADAM-10-selective inhibitor GI254023x, as the level of expressed ADAM-10 is on average 9.8-fold higher on mRNA level compared with ADAM-17. In addition, GI254023x also prevents CXCL16 shedding from the cell membrane and is even more potent than TAPI-2[2]. When applying the specific ADAM10 (α-secretase) inhibitor GI254023X (5 mM) to serum/glucose-deprived slices, PI counts are significantly increased in comparison with DSMO (carrier)-treated controls[3].

Protocol:

Kinase Assay: [3]Cell cultures are pre-treated with 10–50 nM yeast-derived sAPPa/E1 or 20 nM human IGF1 for 24 h before removal of glucose and/or serum. During starvation for 24–48 h, the same treatments are administered. IGF1 is added every 24 h owing to its short half-life. In the experiment using PTX, 100 μM of the toxin is applied 30 min before sAPPa is added to the medium. Akt kinase activity is measured in vitro with a commercial kit according to the manufacturer’s protocol. Briefly, endogenous levels of pAkt are immunoprecipitated from whole-cell extracts with immobilized pAkt (Ser473) mAb (bead conjugate) overnight. After extensive washing, the kinase assay is performed using 10mM ATP and GSK3 fusion protein (27 kDa) as a substrate. Subsequent inactivation of GSK3 is measured by western blot detecting pGSK3a/b (Ser 21/9, 27 kDa)[3]. Cell Assay: [3]Cell death is quantified based on plasma membrane permeabilization. When applying the ADAM10 (a-secretase) inhibitor GI254023X (5 mM), slices are cultured in serum-/glucose-free medium for 48 h containing the inhibitor or its respective carrier (DMSO) as control. Round circles of identical size (Ø 500mm) are positioned in equivalent locations within the CA1 region of each hippocampus image and all PI-stained cells are counted using ImageJ software. Cell viability assays are performed with a commercial kit according to the manufacturer’s instructions. The assay quantitates ATP levels, an indicator of metabolically active cells, photometrically with a fluorescence plate reader. Additionally, we applied the live-dead cell staining kit according to the manual. Cells are simultaneously stained with green fluorescent calcein-AM (4mM; ex/em: 495/515 nm) to detect intracellular esterase activity (viable cells) and red fluorescent ethidium homodimer-3 (2mM; ex/em: 530/635 nm) to indicate loss of plasma membrane integrity (dead cells)[3].

References:

Verena V. Metz, et al. Induction of RAGE Shedding by Activation of G Protein-Coupled Receptors. PLoS One. 2012, doi: 10.1371/journal.pone.0041823

N Milosch, et al. Holo-APP and G-protein-mediated signaling are required for sAPPa-induced activation of the Akt

M J M Gooden, et al. Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity. British Journal of Cancer (2014) 110, 1535–1544 | doi: 10.1038/bjc.2014.55

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