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Small molecules targeting γ-secretase and their potential biological applications

The γ-secretase is a large transmembrane protein complex composed of four distinct units. It has aroused numerous attention over the past two decades as its intriguing role in mediating intramembrane proteolysis. γ-Secretase controls the cleavage of a broad ranged substrates, part of which have impl...

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Published in:European journal of medicinal chemistry 2022-03, Vol.232, p.114169-114169, Article 114169
Main Authors: Wen, Jiachen, Liu, Dan, Zhao, Linxiang
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Language:English
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Liu, Dan
Zhao, Linxiang
description The γ-secretase is a large transmembrane protein complex composed of four distinct units. It has aroused numerous attention over the past two decades as its intriguing role in mediating intramembrane proteolysis. γ-Secretase controls the cleavage of a broad ranged substrates, part of which have implicated in the pathogenesis of Alzheimer's disease, inflammation, and tumorigenesis. The disclosure of the atomic structure of the γ-secretase complex through cryo-EM in recent years has facilitated the understanding of its physiological roles, as well as enabled rational design of novel γ-secretase targeting molecules. This review highlights the recent progress of γ-secretase inhibitors and modulators under either clinical or preclinical stages, as well as their potential uses against various biological indications. [Display omitted] •Summary of structure and functions of γ-secretase complex.•Conclusive review of γ-secretase targeting small molecules under clinical trials.•Advances of γ-secretase modulators and their potential anti-AD activity.•Advances of γ-secretase inhibitors and their potential biological activity.
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subjects Alzheimer Disease - drug therapy
Alzheimer Disease - pathology
Amyloid Precursor Protein Secretases - metabolism
Anti-Alzheimer's disease
Anti-tumor
Cell Membrane - metabolism
Humans
Notch signaling pathway
γ-Secretase inhibitor
γ-Secretase modulator
title Small molecules targeting γ-secretase and their potential biological applications
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