Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Dec;1828(12):2898-907.
doi: 10.1016/j.bbamem.2013.06.005. Epub 2013 Jun 17.

γ-Secretase inhibitors and modulators

Todd E Golde  1 , Edward H Koo, Kevin M Felsenstein, Barbara A Osborne, Lucio Miele
Affiliations
Review

γ-Secretase inhibitors and modulators

Todd E Golde et al. Biochim Biophys Acta. 2013 Dec.

Abstract

γ-Secretase is a fascinating, multi-subunit, intramembrane cleaving protease that is now being considered as a therapeutic target for a number of diseases. Potent, orally bioavailable γ-secretase inhibitors (GSIs) have been developed and tested in humans with Alzheimer's disease (AD) and cancer. Preclinical studies also suggest the therapeutic potential for GSIs in other disease conditions. However, due to inherent mechanism based-toxicity of non-selective inhibition of γ-secretase, clinical development of GSIs will require empirical testing with careful evaluation of benefit versus risk. In addition to GSIs, compounds referred to as γ-secretase modulators (GSMs) remain in development as AD therapeutics. GSMs do not inhibit γ-secretase, but modulate γ-secretase processivity and thereby shift the profile of the secreted amyloid β peptides (Aβ) peptides produced. Although GSMs are thought to have an inherently safe mechanism of action, their effects on substrates other than the amyloid β protein precursor (APP) have not been extensively investigated. Herein, we will review the current state of development of GSIs and GSMs and explore pertinent biological and pharmacological questions pertaining to the use of these agents for select indications. This article is part of a Special Issue entitled: Intramembrane Proteases.

Keywords: Alzheimer's disease; Cancer; γ-Secretase inhibitor; γ-Secretase modulator.

PubMed Disclaimer

Figures

Figure 1
Figure 1. A model of stepwise γ-secretase cleavage
Typical processing of a Type 1 transmembrane protein (A), by a “sheddase” followed by sequential γ-secretase cleavages results in release of multiple potentially bioactive protein fragments: the ectodomain (B), a transmembrane carboxyl terminal fragment (CTF) or stub) (C), the cytoplasmic domain (D) and an Aβ/p3 like domain (E). Thus, γ-secretase generates potentially bioactive fragments (D) by an initial cleavage and (E) by processive step-wise cleavage GSIs inhibit the initial cleavage and GSMs alter processivity.
Figure 2
Figure 2. Examples of GSIs
Begacestat, BMS-708163 and ELN-475516 have been reported to be Notch-Sparing GSIs.
Figure 3
Figure 3. Examples of GSMs
Indomethacin is an NSAID GSM, GSM-1 is an example of a potent 2nd generation acidic GSM and E2012 is an example of a non-acidic GSM.
See this image and copyright information in PMC

References

    1. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003;422:438–441. - PubMed
    1. De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma- Secretase complex. Neuron. 2003;38:9–12. - PubMed
    1. Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science. 2004;305:1119–1123. - PubMed
    1. Haapasalo A, Kovacs DM. The Many Substrates of Presenilin/gamma-Secretase. J Alzheimers Dis. 2011 - PubMed
    1. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258:126–129. - PubMed

Publication types

MeSH terms

Substances