Discovery of notch-sparing γ-secretase inhibitors

C. E. Augelli-Szafran, H. X. Wei, D. Lu, J. Zhang, Y. Gu, T. Yang, P. Osenkowski, W. Ye, M. S. Wolfe

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ however, γ-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter γ-secretase activity to reduce Aβ production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that γ-secretase can be selectively inhibited in this way by naphthyl-substituted γ-aminoketones and γ-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing γ-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.

Original languageEnglish (US)
Pages (from-to)207-209
Number of pages3
JournalCurrent Alzheimer Research
Volume7
Issue number3
DOIs
StatePublished - May 1 2010
Externally publishedYes

Fingerprint

Amyloid Precursor Protein Secretases
Drug Evaluation
Protein Precursors
Amyloid
Proteolysis
Alzheimer Disease
Peptide Hydrolases
Molecular Weight
Enzymes

Keywords

  • Amyloid
  • Drug discovery
  • Inhibitors
  • Protease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Augelli-Szafran, C. E., Wei, H. X., Lu, D., Zhang, J., Gu, Y., Yang, T., ... Wolfe, M. S. (2010). Discovery of notch-sparing γ-secretase inhibitors. Current Alzheimer Research, 7(3), 207-209. https://doi.org/10.2174/156720510791050920

Discovery of notch-sparing γ-secretase inhibitors. / Augelli-Szafran, C. E.; Wei, H. X.; Lu, D.; Zhang, J.; Gu, Y.; Yang, T.; Osenkowski, P.; Ye, W.; Wolfe, M. S.

In: Current Alzheimer Research, Vol. 7, No. 3, 01.05.2010, p. 207-209.

Research output: Contribution to journalArticle

Augelli-Szafran, CE, Wei, HX, Lu, D, Zhang, J, Gu, Y, Yang, T, Osenkowski, P, Ye, W & Wolfe, MS 2010, 'Discovery of notch-sparing γ-secretase inhibitors', Current Alzheimer Research, vol. 7, no. 3, pp. 207-209. https://doi.org/10.2174/156720510791050920
Augelli-Szafran CE, Wei HX, Lu D, Zhang J, Gu Y, Yang T et al. Discovery of notch-sparing γ-secretase inhibitors. Current Alzheimer Research. 2010 May 1;7(3):207-209. https://doi.org/10.2174/156720510791050920
Augelli-Szafran, C. E. ; Wei, H. X. ; Lu, D. ; Zhang, J. ; Gu, Y. ; Yang, T. ; Osenkowski, P. ; Ye, W. ; Wolfe, M. S. / Discovery of notch-sparing γ-secretase inhibitors. In: Current Alzheimer Research. 2010 ; Vol. 7, No. 3. pp. 207-209.
@article{aeed0d128c8642858cc98f990bc1805c,
title = "Discovery of notch-sparing γ-secretase inhibitors",
abstract = "Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ however, γ-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter γ-secretase activity to reduce Aβ production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that γ-secretase can be selectively inhibited in this way by naphthyl-substituted γ-aminoketones and γ-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing γ-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.",
keywords = "Amyloid, Drug discovery, Inhibitors, Protease",
author = "Augelli-Szafran, {C. E.} and Wei, {H. X.} and D. Lu and J. Zhang and Y. Gu and T. Yang and P. Osenkowski and W. Ye and Wolfe, {M. S.}",
year = "2010",
month = "5",
day = "1",
doi = "10.2174/156720510791050920",
language = "English (US)",
volume = "7",
pages = "207--209",
journal = "Current Alzheimer Research",
issn = "1567-2050",
publisher = "Bentham Science Publishers B.V.",
number = "3",

}

TY - JOUR

T1 - Discovery of notch-sparing γ-secretase inhibitors

AU - Augelli-Szafran, C. E.

AU - Wei, H. X.

AU - Lu, D.

AU - Zhang, J.

AU - Gu, Y.

AU - Yang, T.

AU - Osenkowski, P.

AU - Ye, W.

AU - Wolfe, M. S.

PY - 2010/5/1

Y1 - 2010/5/1

N2 - Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ however, γ-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter γ-secretase activity to reduce Aβ production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that γ-secretase can be selectively inhibited in this way by naphthyl-substituted γ-aminoketones and γ-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing γ-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.

AB - Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ however, γ-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter γ-secretase activity to reduce Aβ production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that γ-secretase can be selectively inhibited in this way by naphthyl-substituted γ-aminoketones and γ-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing γ-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.

KW - Amyloid

KW - Drug discovery

KW - Inhibitors

KW - Protease

UR - http://www.scopus.com/inward/record.url?scp=77952534139&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952534139&partnerID=8YFLogxK

U2 - 10.2174/156720510791050920

DO - 10.2174/156720510791050920

M3 - Article

C2 - 20088802

AN - SCOPUS:77952534139

VL - 7

SP - 207

EP - 209

JO - Current Alzheimer Research

JF - Current Alzheimer Research

SN - 1567-2050

IS - 3

ER -