# SH2scan: Mapping SH2 Domain-Ligand Binding Selectivity for Inhibitors and Degraders

## TL;DR

The paper introduces SH2scan, a new platform to study how synthetic ligands bind to SH2 domains, helping design more selective drugs.

## Contribution

SH2scan is a novel high-throughput assay platform for quantifying ligand-SH2 domain interactions and their selectivity.

## Key findings

- SH2scan quantified ligand binding to over 80% of SH2 domains in the target class.
- The platform revealed unique selectivity profiles and dissociation constants for nine synthetic ligands.
- SH2scan can aid in designing selective compounds and discovering new molecular probes.

## Abstract

Drug discovery targeting
SH2 domains (key protein–protein
interaction modules) has been hampered by a lack of assay systems
evaluating synthetic ligand binding selectivity toward SH2 domains
to reduce potential off-target effects. In addition, the molecular
determinants for the synthetic ligand engagement to SH2 domains across
the target class have yet to be defined. Here, we developed SH2scan, a high-throughput competition binding assay platform
to quantify ligand-SH2 domain interactions, covering >80% of the
target
class. We uncovered unique binding selectivity profiles and quantified
a broad range of dissociation constants (K
Ds) for 9 synthetic ligands of SH2 domains from the scientific literature
with a range of reported primary targets. These results demonstrate
that SH2scan can be used to design more selective
compounds targeting the SH2 domains. The platform can be further leveraged
for the discovery of new molecular probes for the dissection of cellular
protein–protein interaction networks.