Target Validation Information
Target ID T99840
Target Name Gamma-secretase
Target Type
Clinical Trial
Drug Potency against Target (5R,6S)-5,6-bis(benzyloxy)cyclohex-2-enone Drug Info IC50 = 1600 nM [528191]
Drug 311383 Drug Info IC50 = 14 nM [527143]
Drug 311951 Drug Info IC50 = 16 nM [527143]
Drug 311952 Drug Info IC50 = 26 nM [527143]
E2012 Drug Info IC50 = 1.3~58 nM
(5R,6S)-6-(benzyloxy)-5-methoxycyclohex-2-enone Drug Info IC50 = 10200 nM [528191]
Drug 311440 Drug Info IC50 = 9 nM [527143]
(2S,3R)-2-(benzyloxy)-3-methoxycyclohexanone Drug Info IC50 = 13900 nM [528191]
1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6H)-one Drug Info IC50 = 1000 nM [528191]
Action against Disease Model E2012 Among the six cell lines tested, only Jurkat and HepG2 showed a decrease in cell proliferation during 4 days of treatment with a gamma-secretase inhibitor [553061] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Most of the Alzheimer's disease (AD)-linked mutations in amyloid precursor protein (APP), which cause abnormal production of beta-amyloid (Abeta), are localized at the major beta-secretase-and gamma-secretase cleavage sites. In this study, using an APP-knockout mouse neuronal cell line, our data demonstrated that at the P2-P1 positions of the epsilon-cleavage site at Abeta49and the zeta-cleavage site at Abeta46, aromatic amino acids caused a strong reduction in total Abeta. On the other hand, residues with a long side chain caused a decrease in Abeta(40) and a concomitant increase in Abeta(42) and Abeta(38). These findings indicate that the structures of the substituting residues at these key positions strongly determine the efficiency and preference of gamma-secretase-mediated APP processing, which determines the ratio of different secreted Abeta species, a crucial factor in the disease development. Our findings provide new insight into the mechanisms of gamma-secretase-mediated APP processing and, specifically, into why most AD-linked APP mutations are localized at major gamma-secretase cleavage sites. This information may contribute to the development of methods of prevention and treatment of Alzheimer's disease aimed at modulating gamma-secretase activity. [553061]
References
Ref 553061Acute effect on the A isoform pattern in CSF in response to -secretase modulator and inhibitor treatment in dogs. J Alzheimers Dis. 2010;21(3):1005-12. doi: 10.3233/JAD-2010-100573.
Ref 528191Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6. Epub 2006 May 8.Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.
Ref 527143J Med Chem. 2004 Jul 29;47(16):3931-3.Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase.
Ref 527143J Med Chem. 2004 Jul 29;47(16):3931-3.Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase.
Ref 527143J Med Chem. 2004 Jul 29;47(16):3931-3.Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase.
Ref 528191Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6. Epub 2006 May 8.Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.
Ref 527143J Med Chem. 2004 Jul 29;47(16):3931-3.Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase.
Ref 528191Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6. Epub 2006 May 8.Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.
Ref 528191Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6. Epub 2006 May 8.Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.

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