Discovery of Potent and Orally bioavailable Benzoazepinamine-Based SHP2 Allosteric Inhibitors for the Treatment of Inflammatory Diseases

Src homology-2 (SH2) domain-containing phosphatase-2
(SHP2) plays
a crucial role in multiple cellular processes and is implicated in
various human diseases. While most SHP2 inhibitors under development
primarily target cancer, their potential in inflammatory diseases
remains largely unexplored. In this study, we identified a novel series
of benzoazepinamine-based SHP2 allosteric inhibitors. Notably, lead
compound 6 demonstrated potent SHP2 inhibitory activity
and significantly suppressed the production of key inflammatory mediators
in the LPS-stimulated macrophages. Mechanistic studies revealed that 6 blocked the NF-κB pathway and inhibited the M1 macrophage
polarization. Furthermore, compound 6 exhibited favorable
pharmacokinetic properties and an acceptable toxicity profile. In
vivo studies confirmed its therapeutic efficacy in reducing inflammation
in both sepsis and acute lung injury mouse models. Together, these
findings highlight SHP2 inhibition by compound 6 as a
promising strategy for the treatment of inflammatory diseases.