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L-685,458
Potent, selective cell-permeable g-secretase inhibitor
L1790
Alzheimer's disease (AD) accounts for the majority of the dementia diagnosed after the age of 60, with over 12 million sufferers worldwide. The disease is characterized by the progressive loss of cognitive function and results in end-stage patients that are bedridden and dependent on custodial care.
The pathogenesis of AD is believed to result from the progressive accumulation in the brain of b-amyloid (Ab), a 4 kDa protein. Ab originates from the proteolytic cleavage of amyloid precursor protein (APP) by two proteases, b-secretase and g-secretase (Figure 1). Cleavage by b-secretase at the amino terminus of APP results in a soluble b-APP and a 12 kDa membrane-bound carboxyl terminal fragment (CTF). The latter in turn becomes the substrate for g-secretase to yield a soluble Ab peptide, Amyloid b protein fragment (1-40) (Ab (1-40)), or the slightly longer, insoluble peptide Amyloid b protein fragment (1-42) (Ab (1-42)). APP can also be cleaved by a third enzyme, a-secretase, leading to the production of soluble a-APP peptide and a 10 kDa CTF. Although Ab (1-42) and Ab (1-40) account for approximately 10% and 90%, respectively, of the total Ab secreted from cells, Ab (1-42) constitutes the major component of the nonfibrillar extracellular plaques that precede the development of the dense, fibrillar neuritic plaques characteristic of AD [1]. Because inhibition of g-secretase blocks the production of Ab, the identification of compounds that block the activity of this enzyme has become a major focus of AD research.
L-685,458 is a novel, potent and selective cell-permeable g-secretase inhibitor [2-5].
- Exhibits over 100-fold greater selectivity for g-secretase than for a panel of other proteases [2].
- Potently inhibits g-secretase and thus the production of Ab total (IC50 17 nM), Ab (1-40), (IC50 48 nM) and Ab (1-42) (IC50 67 nM) in human neuroblastoma SHSY5Y cells overexpressing spbA4CTF, a truncated form of human APP [2].
Manufactured and sold under non-exclusive license from Merck & Co. Inc.
Related secretase and b-amyloid products:
| Secretase Inhibitors |
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| Product Name |
Product # |
| b-Secretase Inhibitor |
S4562 |
| g-Secretase Inhibitor |
S2188 |
| MG132 |
C2211 |
| Glu-Val-Asn-[(2R,4S,5S)-5-amino-4-hydroxy-2,7-dimethyloctanoyl]-Ala-Glu-Phe |
G8291 |
| Secretase |
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| b-secretase (BACE1) |
S5067 |
| Secretase Kit |
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| b-Secretase (BACE1) Activity Detection Kit (Fluorescent) |
CS0010 |
| Secretase Antibodies |
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| Anti-BACE-1 (EE-17) Rabbit, IgG fraction of antiserum |
B0681 |
| Anti-BACE-1 (LK-16) Rabbit, IgG fraction of antiserum |
B0806 |
| Other Secretase Products |
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| 7- Methoxycoumarin-4-acetyl-Glu-Val-Lys-Met-Asp-Ala-Glu-Phe-(2,4-dinitrophenyl)-Lys-OH trifluoroacetate salt (FRET peptide for detecting b-secretase) |
M4689 |
| 7-Methoxycoumarin-4-acetyl-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-(2,4-dinitrophenyl)-Lys trifluoroacetate salt (FRET peptide for detecting a-secretase) |
M4564 |
| Mca-[Asn670, Leu671]-Amyloid b/A4 Precursor Protein 770 fragment 667-675-(Dnp)Lys amide (Peptide containing the b-secretase site of Swedish mutation of APP; fluorogenic b-secretase substrate) |
M1063 |
| b-Amyloid inhibitors |
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| Cloquinol |
C8133 |
| Dabcyl-[Asn670,Leu671]-Amyloid b/A4 Protein Precursor770 Fragment (661-675)-Edans |
A4972 |
| Flufenamic acid |
F9005 |
| Pepstatin A |
P5318 |
| b-Amyloid |
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| Ab (1-40) |
A1075 |
| Ab (1-42) |
A9810 |
| b-Amyloid Probes |
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| BTA-1 |
B9934 |
| Chrysamine G |
C1115 |
| b-Amyloid Kits |
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| b-Amyloid 1-40 ELISA, human |
BE0100 |
| b-Amyloid 1-42 ELISA, human |
BE0200 |
| b-Amyloid Antibodies |
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| Monoclonal Anti-b Amyloid [17-24] Human (Clone 4G8) Mouse, purified IgG2b |
A1349 |
| Monoclonal Anti-b Amyloid [1-17] (Human Clone 6E10) Mouse, purified IgG1 |
A1474 |
| Anti-Amyloid Peptide b Cleavage Site 42 Rabbit, Affinity isolated antibody, Buffered aqueous solution |
A1976 |
| Anti-Amyloid Peptide b, Cleavage Site 43 Rabbit, Affinity isolated antibody, Buffered aqueous solution |
A2101 |
| Monoclonal Anti-Amyloid b-Protein (Clone BAM-10) Mouse, ascites fluid, isotype IgG1 |
A5213 |
| Anti-Amyloid b-Protein (1-40) Rabbit, whole antiserum |
A8326 |
| Anti-Amyloid Precursor Protein, C-Terminal Rabbit, IgG fraction of antiserum |
A8717 |
| Anti-Amyloid Precursor Protein, KPI Insert Rabbit, IgG fraction of antiserum |
A8842 |
| Anti-Amyloid Precursor Protein, N-Terminal Rabbit, IgG fraction of antiserum |
A8967 |
| Anti-ERAB (endoplasmic reticulum Rabbit, IgG fraction of antiserum Rabbit, affinity isolated antibody |
E1151 |
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Figure 1. Cleavage of Amyloid Precursor Protein.
Amyloid precursor protein (APP) is sequentially cleaved by b-secretase and then g-secretase to form soluble amyloid precursor protein b (sAPPb) and the amyloid b 42 protein fragment (Ab42). The Ab42 fragments then aggregate and form the extracellular plaques common to Alzheimer's disease.
References
- Hardy, J. and Selkoe, D.J., Science, 297, 353-356 (2002).
- Shearman, M.S., et al., Biochemistry, 39, 8698-8704 (2000).
- Li, Y-M., et al., Proc. Nat. Acad. Sci. USA, 97, 6138-6143 (2000).
- Li, Y-M., et al., Nature, 405, 689-694 (2000).
- Tian G., et al., J. Biol. Chem., 277, 31499-31505 (2002).
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