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 t...
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0293548&type=printable |
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| author | Frances M Bashore Vittorio L Katis Yuhong Du Arunima Sikdar Dongxue Wang William J Bradshaw Karolina A Rygiel Tina M Leisner Rod Chalk Swati Mishra C Andrew Williams Opher Gileadi Paul E Brennan Jesse C Wiley Jake Gockley Gregory A Cary Gregory W Carter Jessica E Young Kenneth H Pearce Haian Fu Emory-Sage-SGC TREAT-AD Center Alison D Axtman |
| author_facet | Frances M Bashore Vittorio L Katis Yuhong Du Arunima Sikdar Dongxue Wang William J Bradshaw Karolina A Rygiel Tina M Leisner Rod Chalk Swati Mishra C Andrew Williams Opher Gileadi Paul E Brennan Jesse C Wiley Jake Gockley Gregory A Cary Gregory W Carter Jessica E Young Kenneth H Pearce Haian Fu Emory-Sage-SGC TREAT-AD Center Alison D Axtman |
| author_sort | Frances M Bashore |
| collection | DOAJ |
| 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, however, these compounds lack selectivity and this limits their utility as chemical tools. |
| format | Article |
| id | doaj-art-a694cd69ff044329bed258122700d8e8 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-a694cd69ff044329bed258122700d8e82025-02-05T05:32:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-01192e029354810.1371/journal.pone.0293548Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.Frances M BashoreVittorio L KatisYuhong DuArunima SikdarDongxue WangWilliam J BradshawKarolina A RygielTina M LeisnerRod ChalkSwati MishraC Andrew WilliamsOpher GileadiPaul E BrennanJesse C WileyJake GockleyGregory A CaryGregory W CarterJessica E YoungKenneth H PearceHaian FuEmory-Sage-SGC TREAT-AD CenterAlison D AxtmanRNA 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0293548&type=printable |
| spellingShingle | Frances M Bashore Vittorio L Katis Yuhong Du Arunima Sikdar Dongxue Wang William J Bradshaw Karolina A Rygiel Tina M Leisner Rod Chalk Swati Mishra C Andrew Williams Opher Gileadi Paul E Brennan Jesse C Wiley Jake Gockley Gregory A Cary Gregory W Carter Jessica E Young Kenneth H Pearce Haian Fu Emory-Sage-SGC TREAT-AD Center Alison D Axtman Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM. PLoS ONE |
| 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 |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0293548&type=printable |
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