L-685,458

γ-secretase inhibitor CAS# 292632-98-5

L-685,458

Catalog No. BCC2344----Order now to get a substantial discount!

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Chemical structure

L-685,458

3D structure

Chemical Properties of L-685,458

Cas No. 292632-98-5 SDF Download SDF
PubChem ID 5479543 Appearance Powder
Formula C39H52N4O6 M.Wt 672.85
Type of Compound N/A Storage Desiccate at -20°C
Synonyms L-685,458
Solubility DMSO : 83.3 mg/mL (123.80 mM; Need ultrasonic and warming)
Chemical Name tert-butyl N-[(2S,3R,5R)-6-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-benzyl-3-hydroxy-6-oxo-1-phenylhexan-2-yl]carbamate
SMILES CC(C)CC(C(=O)NC(CC1=CC=CC=C1)C(=O)N)NC(=O)C(CC2=CC=CC=C2)CC(C(CC3=CC=CC=C3)NC(=O)OC(C)(C)C)O
Standard InChIKey MURCDOXDAHPNRQ-ZJKZPDEISA-N
Standard InChI InChI=1S/C39H52N4O6/c1-26(2)21-33(37(47)41-32(35(40)45)24-29-19-13-8-14-20-29)42-36(46)30(22-27-15-9-6-10-16-27)25-34(44)31(23-28-17-11-7-12-18-28)43-38(48)49-39(3,4)5/h6-20,26,30-34,44H,21-25H2,1-5H3,(H2,40,45)(H,41,47)(H,42,46)(H,43,48)/t30-,31+,32+,33+,34-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of L-685,458

DescriptionPotent and selective γ-secretase inhibitor (IC50 = 17 nM) that displays > 50-fold selectivity over a range of aspartyl, serine and cysteine proteases. Exhibits equal potency for inhibition of Aβ40 and Aβ42 peptides (IC50 values are 48 and 67 nM respectively in human neuroblastoma cells). Also regulates CXCR4 and VEGFR2 expression through inhibition of Notch signaling in vitro.

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Preparing Stock Solutions of L-685,458

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.4862 mL 7.4311 mL 14.8622 mL 29.7243 mL 37.1554 mL
5 mM 0.2972 mL 1.4862 mL 2.9724 mL 5.9449 mL 7.4311 mL
10 mM 0.1486 mL 0.7431 mL 1.4862 mL 2.9724 mL 3.7155 mL
50 mM 0.0297 mL 0.1486 mL 0.2972 mL 0.5945 mL 0.7431 mL
100 mM 0.0149 mL 0.0743 mL 0.1486 mL 0.2972 mL 0.3716 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on L-685,458

L-685,458 is a selective and Potent inhibitor of γ-secretase with IC50 value of 17 nM[1].
γ-Secretase is one of intramenbrane-cleaving aspartyl protease which cleaves many type-I membrane proteins and many of them have important biological functions. γ-Secretase is a multi-subunit protease and it contains presenilin, nicastrin, APH-1(Anterior Pharynx- defective 1) and PEN-2. Presenilin contains Asp258 and Asp385 embedded in the sixth and seventh transmembrane domain and forms the active site. The feature of being a membrane integrated protease complex makes it difficult to be purified as well as studying its mechanism. γ-secretase is responsible for the generation Aβfrom the amyloid precusor protein. γ-Secretase has been considered as an important drug target for Alzheimer's disease. γ-Secertase also is responsible for Notch processing which is related to cancer such as leukemia.
L-685,458 is a transition state analogue inhibitor.
It is a pan-inhibitor of γ-secretase which decrease the products of Aβ(42) and Aβ(40) peptides. It displays a selectivity of 50-fold or greater inhibition than a range of aspartyl, serine, and cysteine protease in vitro membrane assay. L-685,458 reduced the product both total Aβand Aβ42 in human primary neuronal cells with IC50 value of 115 nM for Aβand Aβ42 for 200 nM[2]. L-685,458 also inhibitedγ-secretase activity by characterizing the production of total secreted Aβby ELISA with IC50 value of about 5 nM in HEK 293 cells overexpressing human APP751.
L-685,458 reduced the cortical total Aβwith a 50% reduction occurring at 100 mg/kg in a dose-dependent manner in PDAPP, and similar reductions in cortical Aβ42 were observed. L-685,458 decreased brain levels of Aβwhen given orally to Tg2576 mice that are transgenic for human APPV717F mutation. [3] L-685,458 also inhibit the Notch signaling, then affects embryonic development in zebrafish embryos[4].
References:
1.Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, Nadin A, Smith AL, Stevenson G, Castro JL: L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 2000, 39(30):8698-8704.
2.Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ et al: Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001, 76(1):173-181.
3.Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B, Merchant KM: The gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 2003, 305(3):864-871.
4.Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C: A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 2002, 3(7):688-694.

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References on L-685,458

[3H]-L-685,458 as a radiotracer that maps gamma-secretase complex in the rat brain: relevance to Abeta genesis and presence of active presenilin-1 components.[Pubmed:17512915]

Brain Res. 2007 Jul 9;1157:81-91.

Gamma-secretase is a multimeric enzyme important for normal cell/neuronal proliferation, differentiation and plasticity. Determining in vivo gamma-secretase expression and activity remains a challenge because its subunit proteins can exist in immature and preassembled forms, but may execute cellular roles irrelevant to gamma-site cleavage. In this study, we characterized [3H]-L-685,458 as a radiotracer for the detection of active gamma-secretase in adult rat brain. In vitro autoradiography indicated that [3H]-L-685,458 binding was saturatable, displaceable by peptidomimetic and small molecule gamma-secretase inhibitors, and exhibited rapid association and dissociation kinetics. In cultured hippocampal slices, [3H]-L-685,458 binding density correlated with Abeta reduction following in-dish dosing of this radioligand or a non-radioactive gamma-secretase inhibitor. [3H]-L-685,458 binding sites in the adult brain were differentially distributed across regions and laminas, with heavy binding localized to the olfactory glomeruli, hippocampal CA3 and cerebellar molecular layer, and moderate binding in the cerebral cortex, amygdala and selected subcortical regions. All of these regions showed labeling for presenilin-1 N-terminal fragments (PS1-NTFs). A distinct correlation of dense binding sites with abundant presence of PS1-NTFs was verified in hippocampal mossy fiber terminals and olfactory bulb glomeruli, suggestive of a rich expression of gamma-secretase in the synapses at these locations that are characteristic of dynamic plasticity. Together, [3H]-L-685,458 is an excellent radiotracer for mapping active gamma-secretase complex, and may serve as a useful tool for studying the enzyme in vivo and in vitro.

L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity.[Pubmed:10913280]

Biochemistry. 2000 Aug 1;39(30):8698-704.

Progressive cerebral amyloid beta-protein (A beta) deposition is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Elevated levels of A beta(42) peptide formation have been linked to early-onset familial AD-causing gene mutations in the amyloid beta-protein precursor (A beta PP) and the presenilins. Sequential cleavage of A beta PP by the beta- and gamma-secretases generates the N- and C-termini of the A beta peptide, making both the beta- and gamma-secretase enzymes potential therapeutic targets for AD. The identity of the A beta PP gamma-secretase and the mechanism by which the C-termini of A beta are formed remain uncertain, although it has been suggested that the presenilins themselves are novel intramembrane-cleaving gamma-secretases of the aspartyl protease class [Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., and Selkoe, D. J. (1999) Nature 398, 513-517]. In this study we report the identification of L-685,458 as a structurally novel inhibitor of A beta PP gamma-secretase activity, with a similar potency for inhibition of A beta(42) and A beta(40) peptides. This compound contains an hydroxyethylene dipeptide isostere which suggests that it could function as a transition state analogue mimic of an aspartyl protease. The preferred stereochemistry of the hydroxyethylene dipeptide isostere was found to be the opposite to that required for inhibition of the HIV-1 aspartyl protease, a factor which may contribute to the observed specificity of this compound. Specific and potent inhibitors of A beta PP gamma-secretase activity such as L-685,458 will enable important advances toward the identification and elucidation of the mechanism of action of this enigmatic protease.

Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells.[Pubmed:18339870]

Cancer Res. 2008 Mar 15;68(6):1889-95.

Gene-targeting studies have shown that Delta-like 4 (Dll4) is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are not well defined. We generated primary human umbilical vascular endothelial cells that express Dll4 protein to study Dll4 function and previously showed that Dll4 down-regulates vascular endothelial growth factor (VEGF) receptor 2 and NRP1 expression and inhibits VEGF function. We now report that expression of Dll4 in endothelial cells inhibited attachment and migration to stromal-derived growth factor 1 (SDF1) chemokine. Cell surface, total protein, and mRNA levels of CXCR4, principal signaling receptor for SDF1, were significantly decreased in Dll4-transduced endothelial cells, attributable to a significant reduction of CXCR4 promoter activity. An immobilized recombinant extracellular portion of Dll4 (rhDLL4) was sufficient to down-regulate CXCR4 mRNA and protein, whereas protein levels of SDF1, VEGF, and RDC1 were unchanged. The gamma-secretase inhibitor L-685,458 significantly reconstituted CXCR4 mRNA in rhDLL4-stimulated endothelial cells. CXCR4 mRNA levels were significantly reduced in mouse xenografts of Dll4-transduced human gliomas compared with control gliomas, and vascular CXCR4 was not detected by immunohistochemistry in the enlarged vessels within the Dll4 gliomas. Thus, Dll4 may contribute to vascular differentiation and inhibition of the angiogenic response by regulating multiple receptor pathways.

Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function.[Pubmed:16219802]

Blood. 2006 Feb 1;107(3):931-9.

Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it is induced by vascular endothelial growth factor (VEGF)-A and hypoxia. Gene targeting studies have shown that Dll4 is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are currently not defined. In this study, we generated primary human endothelial cells that overexpress Dll4 protein to study Dll4 function and mechanism of action. Human umbilical vein endothelial cells retrovirally transduced with Dll4 displayed reduced proliferative and migratory responses selectively to VEGF-A. Expression of VEGF receptor-2, the principal signaling receptor for VEGF-A in endothelial cells, and coreceptor neuropilin-1 was significantly decreased in Dll4-transduced endothelial cells. Consistent with Dll4 signaling through Notch, expression of HEY2, one of the transcription factors that mediates Notch function, was significantly induced in Dll4-overexpressing endothelial cells. The gamma-secretase inhibitor L-685458 significantly reconstituted endothelial cell proliferation inhibited by immobilized extracellular Dll4 and reconstituted VEGFR2 expression in Dll4-overexpressing endothelial cells. These results identify the Notch ligand Dll4 as a selective inhibitor of VEGF-A biologic activities down-regulating 2 VEGF receptors expressed on endothelial cells and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis.

Description

L-685458 is a potent inhibitor of Amyloid β-Protein precursor γ-secretase activity with IC50 of 17 nM, shows greater than 50-100-fold selectivity over other aspartyl proteases tested.

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