Evidence map›Paper›PMID 37547005›Full record

ArticlebioRxiv : the preprint server for biology2023

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

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 and 12 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 4 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors at 8 institutions in 3 countries.

Frances M BashoreUNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Structural Genomics Consortium, University of North Carolina, Chapel Hill, NC, USA.
Vittorio L KatisARUK 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.
Yuhong DuDepartment 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.
Arunima SikdarUNC 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.
Dongxue WangDepartment 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.
William J BradshawARUK 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.
Karolina A RygielARUK 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.
Tina M LeisnerUNC 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.
Rod ChalkARUK 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.
Swati MishraUniversity of Washington, Seattle, WA 98109.
Andrew C WilliamsUniversity of Washington, Seattle, WA 98109.
Opher GileadiARUK 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.
Paul E BrennanARUK 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.
Jesse C WileySAGE Bionetworks, Seattle, WA, USA.
Jake GockleySAGE Bionetworks, Seattle, WA, USA.
Gregory A CaryThe Jackson Laboratory, Bar Harbor, ME, USA.
Gregory W CarterThe Jackson Laboratory, Bar Harbor, ME, USA.
Jessica E YoungUniversity of Washington, Seattle, WA 98109.
Kenneth H PearceUNC 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.
Haian FuDepartment 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.
Emory-Sage-SGC TREAT-AD Center
Alison D AxtmanUNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Structural Genomics Consortium, University of North Carolina, Chapel Hill, NC, USA.
University of Oxford · GBEmory University · USUniversity of North Carolina at Chapel Hill · USUniversity of Washington · USJackson Laboratory · USJoint Center for Structural Genomics · USSage Bionetworks · USKarolinska University Hospital · SE

Funding

TREAT AD Structural Biology CoreU54AG065187 · NIA · EMORY UNIVERSITY · PI Gregory W Carter, ALLAN I LEVEY · 2019 to 2026
$69.7M
NIA NIH HHS U54 AG065187Wellcome Trust
6 · The paper itself

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.

Identifiers

PMID37547005
PMCPMC10402180
OpenAlexW4385374714

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.