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 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.