title: γ-Secretase inhibitors and modulators.
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.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA. Electronic address: tgolde@ufl.edu.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Felsenstein
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Osborne
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D021122:Protein Subunits; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Cancer; γ-Secretase inhibitor; γ-Secretase modulator