title: Learning by failing: ideas and concepts to tackle γ-secretases in Alzheimer's disease and beyond.
abstract: γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all γ-secretases causes serious toxicity. Evolving insights suggest that selective inhibition of one of these proteases, or more subtle modulation of γ-secretases by stimulating their carboxypeptidase-like activity but sparing their endopeptidase activity, are potentially highly interesting approaches. The rapidly growing knowledge of regulation, assembly, and specificity of these intriguing protein complexes and the potential advent of high-resolution structural information could dramatically change the perspective on safe and efficacious γ-secretase inhibition in various disorders.
authors.affiliation: VIB Center for the Biology of Disease, Vlaams Instituut voor Biotechnologie, BE-3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Lucía
authors.initials: L
authors.lastname: Chávez Gutiérrez
mesh_terms: D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods*; D011480:Protease Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D017211:Treatment Failure
chemical_list: D016564:Amyloid beta-Protein Precursor; D001381:Azepines; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine
keywords: clinical trials; intramembrane proteolysis; modulators; structure; therapy