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Purity: ≥98%
GI254023X (also known as GI4023 and SRI028594) is a novel and potent inhibitor of MMP9 (Matrix Metallopeptidase 9) and ADAM10 (A Disintegrin and Metalloproteinase 10) with IC50s of 2.5 and 5.3 nM, respectively. ADAM10 has been identified as the major physiological alpha-secretase in neurons, responsible for cleaving APP in a non-amyloidogenic manner. Accumulating evidence indicates that loss of physiologic amyloid precursor protein (APP) function leads to reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging. The ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) inhibitor GI254023X exacerbated neuron death in organotypic (hippocampal) slice cultures of wt mice subjected to trophic factor and glucose deprivation. This cell death-enhancing effect of GI254023X could be completely rescued by applying exogenous sAPPα. Interestingly, sAPPα-dependent Akt induction was unaffected in neurons of APP-ΔCT15 mice that lack the C-terminal YENPTY motif of the APP intracellular region. In contrast, sAPPα-dependent rescue of Akt activation was completely abolished in APP mutant cells lacking the G-protein interaction motif located in the APP C-terminus and by blocking G-protein-dependent signaling with pertussis toxin. Collectively, our data provide new mechanistic insights into the physiologic role of APP in antagonizing neurotoxic stress: they suggest that cell surface APP mediates sAPPα-induced neuroprotection via G-protein-coupled activation of the Akt pathway.
| ln Vitro |
Constitutive RAGE gain was greatly reduced in cell analysis by GI254023X at concentrations of 25 μM and even 1 μM; PACAP-induced RAGE gain was similarly significantly reduced. A tiny increase in RAGE bias is still seen at 100 nM in concentration. GI254023X distinguished between ADAM17 (IC50=541 nM) and ADAM10 (IC50=5.3 nM)/MMP9 (IC50=2.5 nM) in in vitro experiments with recombinant recombinants [1]. Dyes that stain ADAM (GI254023x, for example) can topologize CXCL16 closure. The GI25 and 4023x chromosomes are selectively replaced by ADAM-10 in A2780 cells carrying the ADAM-10/ADAM-17 twin TAPI-2 ADAM-10 because the average level of expressed ADAM-10 mRNA is 9.8 times higher than that of Adam-17. Furthermore, even more successfully than TAPI-2, GI254023x stops CXCL16 from shedding from the cell membrane [2]. In comparison to pairs treated with DMSO (vehicle), there was a statistically significant rise in PI when the particular ADAM10 (alpha-death enzyme) dead GI254023X (5 mM) serum/dead slices were administered [3].
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| Additional Infomation |
GI254023X is a L-valine derivative that is 3-methyl-L-valine in which carboxy OH group is replaced by a methylnitrilo group and the one of the amino hydrogens is replaced by a (2R)-2-{(1S)-1-[formyl(hydroxy)amino]ethyl}-5-phenylpentanoyl group. It is a potent MMP9 and ADAM10 metalloprotease inhibitor with IC50 of 2.5 and 5.3 nM, respectively. It has a role as an apoptosis inducer, an antineoplastic agent, a matrix metalloproteinase inhibitor and an EC 3.4.24.* (metalloendopeptidase) inhibitor. It is a L-valine derivative, an aldehyde and a member of hydroxylamines.
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| Molecular Formula |
C21H33N3O4
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| Molecular Weight |
391.51
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| Exact Mass |
391.247
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| CAS # |
260264-93-5
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| Related CAS # |
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| PubChem CID |
9952396
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| Appearance |
White to off-white solid powder
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| LogP |
4.455
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
28
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| Complexity |
512
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C[C@@H]([C@@H](CCCC1=CC=CC=C1)C(=O)N[C@H](C(=O)NC)C(C)(C)C)N(C=O)O
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| InChi Key |
GHVMTHKJUAOZJP-CGTJXYLNSA-N
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| InChi Code |
InChI=1S/C21H33N3O4/c1-15(24(28)14-25)17(13-9-12-16-10-7-6-8-11-16)19(26)23-18(20(27)22-5)21(2,3)4/h6-8,10-11,14-15,17-18,28H,9,12-13H2,1-5H3,(H,22,27)(H,23,26)/t15-,17+,18+/m0/s1
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.39 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.39 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5542 mL | 12.7711 mL | 25.5421 mL | |
| 5 mM | 0.5108 mL | 2.5542 mL | 5.1084 mL | |
| 10 mM | 0.2554 mL | 1.2771 mL | 2.5542 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
sAPPαinduces neuroprotection in organotypic hippocampal slices from wt mice but not from APP-deficient mice.Cell Death Dis.2014 Aug 28;5:e1391. |
ADAM proteases regulate CXCL16 shedding.Br J Cancer.2014 Mar 18;110(6):1535-44. |
ADAM proteases regulate migratory behaviour of ovarian cancer (OC) cells.Br J Cancer.2014 Mar 18;110(6):1535-44. |
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