γ-secretase inhibitors: From chemical probes to drug development Book Section


Authors: Hur, J. Y.; Gertsik, N.; Johnson, D. S.; Li, Y. M.
Editor: Wolfe, M. S.
Article/Chapter Title: γ-secretase inhibitors: From chemical probes to drug development
Abstract: γ-Secretase, an intramembrane aspartyl protease that cleaves its substrates within their transmembrane domains, is composed of four subunits: presenilin (PS), nicastrin (Nct), Aph-1, and Pen-2. PS is the catalytic subunit of γ-secretase. Aberrant cleavage of two γ-secretase substrates, namely amyloid precursor protein (APP) and Notch, can lead to Alzheimer's disease (AD) and cancer, respectively. As a result of its role in these diseases, γ-secretase has emerged as an important drug target. In the chapter we review the way in which small molecule inhibition of γ-secretase is being explored as a potential therapy for AD. γ-Secretase inhibitors (GSIs) are intended to block γ-secretase cleavage of APP, thereby lowering the amount of toxic Aβ produced and slowing neurodegeneration. However, these GSIs also block γ-secretase cleavage of other substrates, including the critical signaling molecule Notch. A wide range of GSIs have been tested in animals and humans, but none have successfully passed clinical trials due to toxicity. A deeper understanding of γ-secretase structure and function would help to develop safe and effective γ-secretase-based therapies. © 2016 Elsevier Inc. All rights reserved.
Keywords: clinical trial; amyloid precursor protein; notch; gamma-secretase; active-site directed inhibitors; alzheimer's disease (ad); nonselective gsi; notch-sparing
Book Title: Developing Therapeutics for Alzheimer's Disease: Progress and Challenges. 1st ed
ISBN: 978-0-12-802173-6
Publisher: Elsevier Inc.  
Date Published: 2016-01-01
Start Page: 63
End Page: 76
Language: English
DOI: 10.1016/b978-0-12-802173-6.00004-6
PROVIDER: scopus
DOI/URL:
Notes: Book Chapter: 4 -- Export Date: 2 March 2017 -- Source: Scopus
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MSK Authors
  1. Yueming Li
    107 Li
  2. Ji Yeun Hur
    4 Hur
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