Novel 7‐secretase inhibitors uncover a common nucleotide‐binding site in JAK3, SIRT2, and PS1

γ‐Secretase is an intramembrane‐cleaving protease responsible for the final proteolytic event in the production of the amyloid‐ß peptides (Aß) implicated in Alzheimer's disease (AD). Inhibition of γ‐secretase activity is thus an attractive therapeutic strategy to slow down the pathogenesis of AD. Drugs often target more than one biomolecule because of conserved 3‐dimensional structures in prospective protein binding sites. We have capitalized on this phenomenon of nature to identify new γ‐secretase inhibitors. Here we show that 2‐hydroxy naphthyl derivatives, a previously identified subclass of NAD + analog inhibitors of sirtuin 2 (SIRT2), are direct γ‐secretase inhibitors. Subsequent structure‐activity relationship studies further showed that 2‐hydroxy‐1‐naphthaldehyde is the minimal pharmacophore for γ‐secretase inhibition. In evaluating target protein determinants of inhibition, we identified a common GXG signature nucleotide‐binding site (NBS) shared by the γ‐secretase subunit presenilin‐1 C‐terminal fragment (PS1‐CTF), SIRT2, and Janus kinase 3 (JAK3). Because a detailed 3‐dimensional structure of γ‐secretase is beyond our knowledge, we took advantage of the known crystal structure of human JAK3 to model the NBS of the PS1‐CTF, which includes the catalytic residue D385. Our results suggest that the flexible PS1‐CTF LGLG loop comprises a substrate‐docking site capable of recognizing specifically different γ‐secretase substrates.—Wu, F., Schweizer, C, Rudinskiy, N., Taylor, D. M., Kazantsev, A., Luthi‐Carter, R., Fraering, P. C. Novel γ‐secretase inhibitors uncover a common nucleotide‐binding site in JAK3, SIRT2, and PS1. FASEB J. 24, 2464–2474 (2010). www.fasebj.org