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.