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Submit ReviewL-685,458
Description: Potent and selective γ-secretase inhibitor
Alternative Names: L 458,γ-Secretase Inhibitor X
Chemical Name: (5S)-(tert-Butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexanoyl)-L-leucy-L-phenylalaninamide
Purity: ≥97% (HPLC)
Biological Activity for L-685,458
L-685,458 is a potent and selective γ-secretase inhibitor (IC50 = 17 nM) that displays > 50-fold selectivity over a range of aspartyl, serine and cysteine proteases. L-685,458 binds with high affinity to the related aspartyl protease, signal peptide peptidase (SPP; KD = 5.1 nM), and inhibits SPP expressed in HEK293 cells (IC50 = 10 μM). L-685,458 exhibits equal potency for inhibition of Aβ40 and Aβ42 peptides (IC50 values are 48 and 67 nM respectively in human neuroblastoma cells). It also regulates CXCR4 and VEGFR2 expression through inhibition of Notch signaling in vitro.
Technical Data for L-685,458
| M. Wt | 672.85 |
| Formula | C39H52N4O6 |
| Storage | Store at -20°C |
| Purity | ≥97% (HPLC) |
| CAS Number | 292632-98-5 |
| PubChem ID | 5479543 |
| InChI Key | MURCDOXDAHPNRQ-ZJKZPDEISA-N |
| Smiles | O[C@H](C[C@@H](CC1=CC=CC=C1)C(N[C@@H](CC(C)C)C(N[C@@H](CC3=CC=CC=C3)C(N)=O)=O)=O)[C@H](CC2=CC=CC=C2)NC(OC(C)(C)C)=O |
The technical data provided above is for guidance only. For batch specific data refer to the Certificate of Analysis.
Tocris products are intended for laboratory research use only, unless stated otherwise.
Solubility Data for L-685,458
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 10.09 | 15 |
Preparing Stock Solutions for L-685,458
The following data is based on the product molecular weight 672.85. Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 0.15 mM | 9.91 mL | 49.54 mL | 99.08 mL |
| 0.75 mM | 1.98 mL | 9.91 mL | 19.82 mL |
| 1.5 mM | 0.99 mL | 4.95 mL | 9.91 mL |
| 7.5 mM | 0.2 mL | 0.99 mL | 1.98 mL |
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Product Datasheets for L-685,458
References for L-685,458
References are publications that support the biological activity of the product.
Shearman et al (2000) L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid-β-protein precursor γ-secretase activity. Biochemistry 39 8698 PMID: 10913280
Williams et al (2006) Up-regulation of the Notch ligand delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107 931 PMID: 16219802
Williams et al (2008) Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells. Cancer Res. 68 1889 PMID: 18339870
Iben et al (2007) Signal peptide peptidase and gamma-secretase share equivalent inhibitor binding pharmacology. J.Biol.Chem. 282 36829 PMID: 17932033
If you know of a relevant reference for L-685,458, please let us know.
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Keywords: L-685,458, L-685,458 supplier, L458, Potent, selective, γ-secretase, gamma-secretase, inhibitors, inhibits, Aβ4, beta40, β42, beta42, Proteinases, Proteases, b-amyloid, β-Amyloid, beta-Amyloid, Precursor, Protein, APP, beta, L685458, amyloidbeta, amyloidb, amyloidβ, inhibitor, X, SPP, SP, L, 458, gamma-Secretase, Inhibitor, Gamma-Secretase, Amyloid, Beta, Peptides, Other, 2627, Tocris Bioscience
8 Citations for L-685,458
Citations are publications that use Tocris products. Selected citations for L-685,458 include:
Liu et al (2018) APP upregulation contributes to retinal ganglion cell degeneration via JNK3. Cell Death Differ 25 661 PMID: 29238071
Kaylan et al (2018) Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling. Elife 7 PMID: 30589410
Chai et al (2017) HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration. Nat Commun 8 1522 PMID: 29142315
Ran et al (2014) γ-Secretase processing and effects of γ-secretase inhibitors and modulators on long Aβ peptides in cells. J Biol Chem 289 3276 PMID: 24352661
Origlia et al (2014) RAGE inhibition in microglia prevents ischemia-dependent synaptic dysfunction in an amyloid-enriched environment. J Neurosci 34 8749 PMID: 24966375
Greife et al (2014) Canonical Notch signalling is inactive in urothelial carcinoma. BMC Cancer 14 628 PMID: 25167871
Mentrup et al (2022) Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis. Nat.Commun. 13 1880 PMID: 35388002
Ran et al (2015) Differential Inhibition of Signal Peptide Peptidase Family Members by Established γ-Secretase Inhibitors. PLoS One 10 e0128619 PMID: 26046535
Do you know of a great paper that uses L-685,458 from Tocris? Please let us know.
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