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

Bashore, Frances M; Katis, Vittorio L; Du, Yuhong; Sikdar, Arunima; Wang, Dongxue; Bradshaw, William J; Rygiel, Karolina A; Leisner, Tina M; Chalk, Rod; Mishra, Swati; Williams, Andrew C; Gileadi, Opher; Brennan, Paul E; Wiley, Jesse C; Gockley, Jake; Cary, Gregory A; Carter, Gregory W; Young, Jessica E; Pearce, Kenneth H; Fu, Haian; Axtman, Alison D

Bashore, Frances M; Katis, Vittorio L; Du, Yuhong; Sikdar, Arunima; Wang, Dongxue; Bradshaw, William J; Rygiel, Karolina A; Leisner, Tina M; Chalk, Rod; Mishra, Swati; Williams, Andrew C; Gileadi, Opher; Brennan, Paul E; Wiley, Jesse C; Gockley, Jake; Cary, Gregory A; Carter, Gregory W; Young, Jessica E; Pearce, Kenneth H; Fu, Haian; Axtman, Alison D.

Afiliação

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.
Brennan PE; Current address: Structural Genomics Consortium, Department of Medicine, Karolinska Hospital and Karolinska Institute, 171 76 Stockholm, Sweden.
Wiley JC; 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.
Gockley J; SAGE Bionetworks, Seattle, WA, USA.
Cary GA; SAGE Bionetworks, Seattle, WA, USA.
Carter GW; The Jackson Laboratory, Bar Harbor, ME, USA.
Young JE; The Jackson Laboratory, Bar Harbor, ME, USA.
Pearce KH; University of Washington, Seattle, WA 98109.
Fu H; 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.

bioRxiv ; 2023 Jul 29.

Article em En | MEDLINE | ID: mdl-37547005

ABSTRACT

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.

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Texto completo: 1 Bases de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos