Matches in SemOpenAlex for { <https://semopenalex.org/work/W4376133639> ?p ?o ?g. }
- W4376133639 endingPage "104794" @default.
- W4376133639 startingPage "104794" @default.
- W4376133639 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." @default.
- W4376133639 created "2023-05-12" @default.
- W4376133639 creator A5003803811 @default.
- W4376133639 creator A5018531874 @default.
- W4376133639 creator A5021772353 @default.
- W4376133639 creator A5022201149 @default.
- W4376133639 creator A5023258601 @default.
- W4376133639 creator A5026125055 @default.
- W4376133639 creator A5029337301 @default.
- W4376133639 creator A5042732536 @default.
- W4376133639 creator A5045766812 @default.
- W4376133639 creator A5060698638 @default.
- W4376133639 creator A5075176939 @default.
- W4376133639 creator A5078699014 @default.
- W4376133639 creator A5079276669 @default.
- W4376133639 date "2023-06-01" @default.
- W4376133639 modified "2023-10-01" @default.
- W4376133639 title "Selective inhibitors of the PSEN1–gamma-secretase complex" @default.
- W4376133639 cites W1534001036 @default.
- W4376133639 cites W1626267121 @default.
- W4376133639 cites W1655404681 @default.
- W4376133639 cites W1675105744 @default.
- W4376133639 cites W1886532866 @default.
- W4376133639 cites W1890431460 @default.
- W4376133639 cites W1975427548 @default.
- W4376133639 cites W1979466033 @default.
- W4376133639 cites W1983924380 @default.
- W4376133639 cites W1985570437 @default.
- W4376133639 cites W1987831563 @default.
- W4376133639 cites W1989654750 @default.
- W4376133639 cites W1992273847 @default.
- W4376133639 cites W2001914338 @default.
- W4376133639 cites W2010724581 @default.
- W4376133639 cites W2016193774 @default.
- W4376133639 cites W2018464285 @default.
- W4376133639 cites W2019007281 @default.
- W4376133639 cites W2028039916 @default.
- W4376133639 cites W2030182984 @default.
- W4376133639 cites W2031142437 @default.
- W4376133639 cites W2031168104 @default.
- W4376133639 cites W2037535298 @default.
- W4376133639 cites W2038342320 @default.
- W4376133639 cites W2047744429 @default.
- W4376133639 cites W2050386832 @default.
- W4376133639 cites W2052186610 @default.
- W4376133639 cites W2054169303 @default.
- W4376133639 cites W2063464173 @default.
- W4376133639 cites W2063999756 @default.
- W4376133639 cites W2082040667 @default.
- W4376133639 cites W2086360580 @default.
- W4376133639 cites W2089824266 @default.
- W4376133639 cites W2092252270 @default.
- W4376133639 cites W2113690827 @default.
- W4376133639 cites W2118935254 @default.
- W4376133639 cites W2120396539 @default.
- W4376133639 cites W2121585056 @default.
- W4376133639 cites W2121867376 @default.
- W4376133639 cites W2128084592 @default.
- W4376133639 cites W2133641393 @default.
- W4376133639 cites W2133962760 @default.
- W4376133639 cites W2134365974 @default.
- W4376133639 cites W2135540923 @default.
- W4376133639 cites W2142653769 @default.
- W4376133639 cites W2144677406 @default.
- W4376133639 cites W2153293603 @default.
- W4376133639 cites W2156910937 @default.
- W4376133639 cites W2159736446 @default.
- W4376133639 cites W2163185773 @default.
- W4376133639 cites W2164215375 @default.
- W4376133639 cites W2164270482 @default.
- W4376133639 cites W2263938816 @default.
- W4376133639 cites W2313461376 @default.
- W4376133639 cites W2321951077 @default.
- W4376133639 cites W2328646303 @default.
- W4376133639 cites W2409963236 @default.
- W4376133639 cites W2742157915 @default.
- W4376133639 cites W2743816750 @default.
- W4376133639 cites W2761324167 @default.
- W4376133639 cites W2775777157 @default.
- W4376133639 cites W2833026885 @default.
- W4376133639 cites W2906429538 @default.
- W4376133639 cites W2908723002 @default.
- W4376133639 cites W2947743912 @default.
- W4376133639 cites W2951411899 @default.
- W4376133639 cites W2991564669 @default.
- W4376133639 cites W3006195452 @default.
- W4376133639 cites W3037926339 @default.
- W4376133639 cites W3115650052 @default.
- W4376133639 cites W4231640017 @default.
- W4376133639 cites W4236388315 @default.
- W4376133639 cites W4252175039 @default.
- W4376133639 cites W4297093959 @default.
- W4376133639 cites W4307138113 @default.
- W4376133639 cites W4310461604 @default.
- W4376133639 cites W4376226284 @default.
- W4376133639 doi "https://doi.org/10.1016/j.jbc.2023.104794" @default.
- W4376133639 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37164155" @default.
- W4376133639 hasPublicationYear "2023" @default.