| Autor: |
Lutgarde Serneels, Rajeshwar Narlawar, Laura Perez Benito, Marti Municoy, Victor Guallar, Dries T’Syen, Maarten Dewilde, François Bischoff, Erwin Fraiponts, Gary Tresadern, Peter W.M. Roevens, Harrie J.M. Gijsen, Bart De Strooper |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Popis: |
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. ispartof: J Biol Chem vol:299 issue:6 pages:104794- ispartof: location:United States status: published |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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