Document Type
Article
Publication Date
2-15-2024
Original Citation
Bashore F,
Katis V,
Du Y,
Sikdar A,
Wang D,
Bradshaw W,
Rygiel K,
Leisner T,
Chalk R,
Mishra S,
Williams C,
Gileadi O,
Brennan P,
Wiley J,
Gockley J,
Cary G,
Carter GW,
Young J,
Pearce K,
Fu H,
,
Axtman A.
Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM. PLoS One. 2024;19(2):e0293548.
Keywords
JMG, Humans, src Homology Domains, Protein-Tyrosine Kinases, Immunoreceptor Tyrosine-Based Activation Motif, Intracellular Signaling Peptides and Proteins, Syk Kinase, Phosphorylation, Receptors, Fc, Enzyme Precursors
JAX Source
PLoS One. 2024;19(2):e0293548.
ISSN
1932-6203
PMID
38359047
DOI
https://doi.org/10.1371/journal.pone.0293548
Grant
The research reported in this manuscript was led by the Emory-Sage-SGC TREAT-AD center and supported by grant U54AG065187 from the National Institute on Aging (NIA). The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute, EU/EFPIA/OICR/McGill/ KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking, Janssen Pharmaceuticals, Merck KGaA Darmstadt Germany (aka EMD in Canada and USA), Pfizer, the São Paulo Research Foundation-FAPESP, and Takeda.
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 SYK-tSH2. 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.
Comments
© 2024 Bashore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.