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

Autor: Bashore FM; UNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Structural Genomics Consortium, University of North Carolina, Chapel Hill, NC, USA., Katis VL; ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Headington, Oxford, OX3 7FZ, UK., Du Y; Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Emory Chemical Biology Discovery Center, School of Medicine, Emory University, Atlanta, GA, USA., Sikdar A; UNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina, Chapel Hill, NC, USA., Wang D; Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Emory Chemical Biology Discovery Center, School of Medicine, Emory University, Atlanta, GA, USA., Bradshaw WJ; ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Headington, Oxford, OX3 7FZ, UK., Rygiel KA; ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Headington, Oxford, OX3 7FZ, UK., Leisner TM; UNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina, Chapel Hill, NC, USA., Chalk R; ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Headington, Oxford, OX3 7FZ, UK., Mishra S; University of Washington, Seattle, WA 98109., Williams AC; University of Washington, Seattle, WA 98109., Gileadi O; ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Headington, Oxford, OX3 7FZ, UK.; Current address: Structural Genomics Consortium, Department of Medicine, Karolinska Hospital and Karolinska Institute, 171 76 Stockholm, Sweden., Brennan PE; ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Headington, Oxford, OX3 7FZ, UK., Wiley JC; SAGE Bionetworks, Seattle, WA, USA., Gockley J; SAGE Bionetworks, Seattle, WA, USA., Cary GA; The Jackson Laboratory, Bar Harbor, ME, USA., Carter GW; The Jackson Laboratory, Bar Harbor, ME, USA., Young JE; University of Washington, Seattle, WA 98109., Pearce KH; UNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina, Chapel Hill, NC, USA., Fu H; Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, USA; Emory Chemical Biology Discovery Center, School of Medicine, Emory University, Atlanta, GA, USA., Axtman AD; UNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Structural Genomics Consortium, University of North Carolina, Chapel Hill, NC, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Jul 29. Date of Electronic Publication: 2023 Jul 29.
DOI: 10.1101/2023.07.28.551026
Abstrakt: 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.
Databáze: MEDLINE