Author:

Keywords:

inhibitors, medicinal chemistry, selectivity, therapy, ƴ-secretase, Humans, Alzheimer Disease, Amyloid Precursor Protein Secretases, Presenilin-1, Multiprotein Complexes, Sulfonamides, Substrate Specificity, Neoplasms, METH/21/005#56741545, 03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences, Biochemistry & Molecular Biology, 31 Biological sciences, 32 Biomedical and clinical sciences, 34 Chemical sciences

Abstract:

Clinical development of γ-secretases, a family of intramembrane cleaving proteases, as therapeutic targets for a variety of disorders including cancer and Alzheimer's disease was aborted because of serious mechanism-based side effects in the phase III trials of unselective inhibitors. Selective inhibition of specific γ-secretase complexes, containing either PSEN1 or PSEN2 as the catalytic subunit and APH1A or APH1B as supporting subunits, does provide a feasible therapeutic window in preclinical models of these disorders. We explore here the pharmacophoric features required for PSEN1 versus PSEN2 selective inhibition. We synthesized a series of brain penetrant 2-azabicyclo[2,2,2]octane sulfonamides and identified a compound with low nanomolar potency and high selectivity (>250-fold) toward the PSEN1-APH1B subcomplex versus PSEN2 subcomplexes. We used modeling and site-directed mutagenesis to identify critical amino acids along the entry part of this inhibitor into the catalytic site of PSEN1. Specific targeting one of the different γ-secretase complexes might provide safer drugs in the future.