title: Identification of gamma-secretase inhibitor potency determinants on presenilin.
abstract: Production of amyloid beta peptides (Abeta), followed by their deposition in the brain as amyloid plaques, contributes to the hallmark pathology of Alzheimer disease. The enzymes responsible for production of Abeta, BACE1 and gamma-secretase, are therapeutic targets for treatment of Alzheimer disease. Two presenilin (PS) homologues, referred to as PS1 and PS2, comprise the catalytic core of gamma-secretase. In comparing presenilin selectivity of several classes of gamma-secretase inhibitors, we observed that sulfonamides in general tend to be more selective for inhibition of PS1-comprising gamma-secretase, as exemplified by ELN318463 and BMS299897. We employed a combination of chimeric constructs and point mutants to identify structural determinants for PS1-selective inhibition by ELN318463. Our studies identified amino acid residues Leu(172), Thr(281), and Leu(282) in PS1 as necessary for PS1-selective inhibition by ELN318463. These residues also contributed in part to the PS1-selective inhibition by BMS299897. Alanine scanning mutagenesis of areas flanking Leu(172), Thr(281), and Leu(282) identified additional amino acids that affect inhibitor potency of not only these sulfonamides but also nonsulfonamide inhibitors, without affecting Abeta production and presenilin endoproteolysis. Interestingly, many of these same residues have been identified previously to be important for gamma-secretase function. These findings implicate TM3 and a second region near the carboxyl terminus of PS1 aminoterminal fragment in mediating the activity of gamma-secretase inhibitors. Our observations demonstrate that PS-selective inhibitors of gamma-secretase are feasible, and such inhibitors may allow differential inhibition of Abeta peptide production and Notch signaling.
authors.affiliation: Elan Pharmaceuticals Inc., 700 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Zhao
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.forename: Martin
authors.initials: M
authors.lastname: Neitzel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Marugg
authors.forename: Jacek
authors.initials: J
authors.lastname: Jagodzinski
authors.forename: Mike
authors.initials: M
authors.lastname: Lee
authors.forename: Kang
authors.initials: K
authors.lastname: Hu
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
authors.forename: Ted
authors.initials: T
authors.lastname: Yednock
authors.forename: Guriqbal
authors.initials: G
authors.lastname: Basi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053764:Presenilin-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D053766:Presenilin-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D002219:Carbamates; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases