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

Area of Science:

• Pharmacology
• Immunology
• Hepatology

Background:

• Colony-stimulating factor 1 receptor (CSF1R) signaling critically regulates macrophage activity in liver inflammation.
• Acetaminophen-induced liver injury involves significant inflammatory responses mediated by macrophages.

Purpose of the Study:

• To discover and characterize novel CSF1R inhibitors for acute-phase treatment of acetaminophen-induced liver injury.
• To evaluate the therapeutic potential of a lead compound, C52, in preclinical models of acute liver injury.

Main Methods:

• Structure-guided drug design and optimization yielded a series of CSF1R inhibitors.
• Compound C52 was assessed for CSF1R inhibition, selectivity, cytotoxicity, and effects on macrophage signaling.
• Efficacy of C52 was evaluated in an acetaminophen-induced acute liver injury mouse model.

Main Results:

• Compound C52 demonstrated potent and selective CSF1R inhibition with low cytotoxicity.
• C52 treatment suppressed M-CSF-induced macrophage signaling pathways (p-CSF1R, p-AKT, p-ERK).
• In vivo, C52 administration reduced liver injury markers (serum transaminases), improved histopathology, decreased inflammatory cell infiltration, and lowered pro-inflammatory cytokines (TNF-α, IL-6).

Conclusions:

• Pharmacologic blockade of CSF1R is a viable strategy for modulating macrophage-driven inflammation in acute liver injury.
• Compound C52 shows promising therapeutic potential for acetaminophen-induced liver injury and warrants further preclinical investigation.