Serneels, Lutgarde;
Narlawar, Rajeshwar;
Perez-Benito, Laura;
Municoy, Marti;
Guallar, Victor;
T'Syen, Dries;
Dewilde, Maarten;
... De Strooper, Bart; + view all
(2023)
Selective inhibitors of the PSEN1–gamma-secretase complex.
Journal of Biological Chemistry (JBC)
, 299
(6)
, Article 104794. 10.1016/j.jbc.2023.104794.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Selective inhibitors of the PSEN1–gamma-secretase complex |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jbc.2023.104794 |
| Publisher version: | https://doi.org/10.1016/j.jbc.2023.104794 |
| Language: | English |
| Additional information: | © 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | ƴ-secretase, inhibitors, selectivity, therapy, medicinal chemistry |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10171916 |
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