L-685,458

Alias:
Cat No.:V0719 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.
L-685,458 Chemical Structure CAS No.: 292632-98-5
Product category: Gamma-secretase
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
Targets
gamma-secretase (Ki = 17 nM)
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]
ln Vivo
L-685,458 decreased cortical total Aβ in PDAPP in a dose-dependent manner, with a 50% reduction at 100 mg/kg, and cortical Aβ42 was also shown to be reduced. When administered orally to Tg2576 mice, transgenic for the human APPV717F mutation, L-685,458 reduced brain levels of Aβ. L-685,458 also inhibits Notch signaling, which has an impact on zebrafish embryonic development.
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.
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.
Animal Protocol
NOD-SCID Mouse Hepatoma Model
5 mg/kg
Percutaneous administration; 5 mg/kg; 2 weeks
References

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

[2]. Oral Dis . 2007 Nov;13(6):555-63.

[3]. Drug Resist Updat . 2008 Dec;11(6):210-8.

[4]. Exp Eye Res . 2014 Jun:123:8-15.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C39H52N4O6
Molecular Weight
672.85
Exact Mass
672.39
Elemental Analysis
C, 69.62; H, 7.79; N, 8.33; O, 14.27
CAS #
292632-98-5
Appearance
Solid powder
SMILES
CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N)NC(=O)[C@H](CC2=CC=CC=C2)C[C@H]([C@H](CC3=CC=CC=C3)NC(=O)OC(C)(C)C)O
InChi Key
MURCDOXDAHPNRQ-ZJKZPDEISA-N
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
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
Synonyms

L685458; L685,458; L-685,458; L 685,458; L-685458; L 685458

HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~100 mg/mL (~148.6 mM)
Water: <1 mg/mL
Ethanol: ~6 mg/mL warmed (~8.9 mM)
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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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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.
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Biological Data
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