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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