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Purity: ≥98%
L-685,458 (also called L685458; L-685458) is a selective inhibitor of Aß PP γ-secretase with potential anti-AD and anticancer activity. It exhibits more than 50-fold selectivity over a variety of aspartyl, serine, and cysteine proteases and inhibits Aß PP γ-secretase with a Ki of 17 nM. With IC50 values of 48 and 67 nM, respectively, L685458 is likewise highly effective in inhibiting the Aβ 40 and Aβ 42 peptides in human neuroblastoma cells. By inhibiting Notch signaling in vitro, it controls the expression of CXCR4 and VEGFR2, as seen in the two cell lines by decreased cytoplasmic distribution and nearly negligible nuclear labeling of Hes1 proteins.
| Targets |
gamma-secretase (Ki = 17 nM)
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| ln Vitro |
L-685,458 has an IC50 of 402 nM, 113 nM, and 48 nM, respectively, for inhibiting Aβ(40) formation in Neuro2A and CHO cell lines overexpressing human AβPP695, and in SHSY5Y cells overexpressing the construct spβA4CTF. Its potency for reducing Aβ(42) is approximately two times lower.[1] L-685,458, through inducing G0–G1 cell cycle arrest and apoptosis, inhibits the growth of Tca8113 cells.[2] Pre-treatment with L-685,458 increases the anti-proliferative effect of imatinib in a T-cell acute lymphoblastic leukemia cell line. [3] L685,458 inhibits signal peptide peptidase (SPP), which also significantly lowers HSV-1 replication in tissue culture.[4]
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| ln Vivo |
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| Enzyme Assay |
Fluorescence resonance energy transfer (FRET) is used in the homogeneous time-resolved fluorescence (HTRF) immunoassay technique between two fluorophores: a donor EuK and a modified allophycocyanine pigment acceptor molecule, XL-665. From nitrogen laser-excited EuK to XL-665, nonradiative FRET occurs when in close proximity and produces an amplified long-lived fluorescence signal. In a nutshell, a standard 96-well plate assay comprises 0.75 nM antibody-EuK, 1.0 nM antibody-biotin, 2.0 nM SA-XL665, and 0.1−0.2 M potassium fluoride in each well. A total assay volume of 200 μL/well is obtained by adding samples of conditioned cell culture medium or synthetic peptide standards and culture medium alone. The addition of 1.0 nM nonbiotinylated antibody in lieu of the biotinylated antibody yields the blank values. Once combined, the reaction mixture is allowed to reach equilibrium binding at 4 °C before being read on the Discovery HTRF microplate analyzer using the manufacturer's instructions.
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| Cell Assay |
MTT is used to measure the in vitro growth rate of L-685,458-treated Tca8113 cells. In short, 96-well plates are seeded with Tca8113 cells. On harvest day, 100 microliters of spent medium are swapped out for the same volume of fresh medium that contains 10% MTT (5 mg ml−1) stock. After four hours of incubation at 37°C, 100 μl of DMSO is added to each well, and the plates are shaken for ten minutes at room temperature. At 570 nm, the absorbance is measured.
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| Animal Protocol |
NOD-SCID Mouse Hepatoma Model
5 mg/kg Percutaneous administration; 5 mg/kg; 2 weeks |
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| References | ||
| Additional Infomation |
L-685,458 is a peptide and carboxamide that is L-leucyl-L-phenylalaninamide, L-Leu-L-Phe-NH2, which has been acylated on the N-terminus by a Phe-Phe hydroxyethylene dipeptide isotere, 2R-benzyl-5S-tert-butoxycarbonylamino-4R-hydroxy-6-phenylhexanoic acid. Compounds based on the structure of L-685,458 are potent inhibitors of gamma-secretase, which mediates the final catalytic step that generates the amyloid beta-peptide (Abeta), which assembles into the neurotoxic aggregates in the brains of sufferers of Alzheimer's disease. It has a role as a peptidomimetic and an EC 3.4.23.46 (memapsin 2) inhibitor. It is a secondary alcohol, a peptide, a carbamate ester and a monocarboxylic acid amide. It contains a tert-butoxycarbonyl group.
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| Molecular Formula |
C39H52N4O6
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| Molecular Weight |
672.85
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| Exact Mass |
672.389
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| Elemental Analysis |
C, 69.62; H, 7.79; N, 8.33; O, 14.27
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| CAS # |
292632-98-5
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| Related CAS # |
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| PubChem CID |
5479543
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| Appearance |
White to off-white solid powder
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| LogP |
6.349
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
49
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| Complexity |
1030
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| Defined Atom Stereocenter Count |
5
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| SMILES |
O([H])[C@@]([H])([C@]([H])(C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C(=O)OC(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[C@@]([H])(C(N([H])[C@]([H])(C(N([H])[C@]([H])(C(N([H])[H])=O)C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]
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| InChi Key |
MURCDOXDAHPNRQ-ZJKZPDEISA-N
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| InChi Code |
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
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| 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
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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) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4862 mL | 7.4311 mL | 14.8622 mL | |
| 5 mM | 0.2972 mL | 1.4862 mL | 2.9724 mL | |
| 10 mM | 0.1486 mL | 0.7431 mL | 1.4862 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.
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