Rational Design and Optimization of Highly Selective CSF1R Inhibitors for the Treatment of Acute Liver Injury.

Colony-stimulating factor 1 receptor (CSF1R) is a key regulator of macrophage-driven liver inflammation. Here, we report a series of CSF1R inhibitors discovered through a structure-guided optimization strategy for the acute-phase treatment of acetaminophen-induced liver injury. For instance, compound C52 exhibited potent CSF1R inhibition, a kinome-wide selective profile, and low cellular cytotoxicity. C52 rapidly suppressed M-CSF-induced phosphorylation events and downstream signaling in macrophages. In an acute liver injury model, therapeutic administration of C52 during the early inflammatory phase markedly reduced serum transaminase levels, improved hepatic histopathology, and alleviated inflammatory cell infiltration, accompanied by suppression of hepatic p-CSF1R/p-AKT/p-ERK signaling and decreased levels of circulating TNF-α and IL-6. Collectively, these results support pharmacologic CSF1R blockade as a timely strategy to modulate macrophage-mediated inflammation in acute liver injury and warrant further preclinical development of C52.