Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM

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  • Bashore F.M.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Katis V.L.
    • Other Affiliation: University of Oxford
  • Du Y.
    • Other Affiliation: Emory University
  • Sikdar A.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Wang D.
    • Other Affiliation: Emory University
  • Bradshaw W.J.
    • Other Affiliation: University of Oxford
  • Rygiel K.A.
    • Other Affiliation: University of Oxford
  • Leisner T.M.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Chalk R.
    • Other Affiliation: University of Oxford
  • Mishra S.
    • Other Affiliation: University of Washington
  • Williams C.A.
    • Other Affiliation: University of Washington
  • Gileadi O.
    • Other Affiliation: Sage Bionetworks
  • Brennan P.E.
    • Other Affiliation: The Jackson Laboratory for Mammalian Genetics
  • Wiley J.C.
    • Other Affiliation: Sage Bionetworks
  • Gockley J.
    • Other Affiliation: Sage Bionetworks
  • Cary G.A.
    • Other Affiliation: The Jackson Laboratory for Mammalian Genetics
  • Carter G.W.
    • Other Affiliation: The Jackson Laboratory for Mammalian Genetics
  • Young J.E.
    • Other Affiliation: University of Washington
  • Pearce K.H.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Fu H.
    • Other Affiliation: Emory University
  • Axtman A.D.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
Abstract
  • RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer’s disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYKtSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • PLoS ONE
Journal volume
  • 19
Journal issue
  • 2-Feb
Language
  • English
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  • Publisher
ISSN
  • 1932-6203
Publisher
  • Public Library of Science

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