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Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM
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 tyrosi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402180/ https://www.ncbi.nlm.nih.gov/pubmed/37547005 http://dx.doi.org/10.1101/2023.07.28.551026 |
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author | 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. |
author_facet | 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. |
author_sort | Bashore, Frances M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10402180 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-104021802023-08-05 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. bioRxiv Article 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. Cold Spring Harbor Laboratory 2023-07-29 /pmc/articles/PMC10402180/ /pubmed/37547005 http://dx.doi.org/10.1101/2023.07.28.551026 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article 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. Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM |
title | Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM |
title_full | Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM |
title_fullStr | Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM |
title_full_unstemmed | Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM |
title_short | Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM |
title_sort | characterization of covalent inhibitors that disrupt the interaction between the tandem sh2 domains of syk and fcer1g phospho-itam |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402180/ https://www.ncbi.nlm.nih.gov/pubmed/37547005 http://dx.doi.org/10.1101/2023.07.28.551026 |
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