Targeting the CSF-1/CSF-1R Axis: Exploring the Potential of CSF1R Inhibitors in Neurodegenerative Diseases
Jihyun Baek, Joonhong Jun, Hye-Jin Kim, Hyunah Bae, Haebeen Park, Hyunwook Cho, Song‐Hee Han, Ho‐Chul Shin, Jung‐Mi Hah
Abstract
We report herein the potential of colony-stimulating factor-1 receptor (CSF1R) inhibitors as therapeutic agents in neuroinflammatory diseases, with a focus on Alzheimer’s disease (AD). Employing a carefully modified scaffold, N -(4-heterocycloalkyl-2-cycloalkylphenyl)-5-methylisoxazole-3-carboxamide, we identify highly selective and potent CSF1R inhibitors─ 7dr i and 7ds i . Molecular docking studies shed light on the binding modes of these key compounds within the CSF1R binding site. Remarkably, kinome-wide selectivity assessment underscores the impressive specificity of 7dr i for CSF-1R. Notably, 7dr i emerges as a potent CSF-1R inhibitor with favorable cellular activity and minimal cytotoxicity among the synthesized compounds. Demonstrating efficacy in inhibiting CSF1R phosphorylation in microglial cells and successfully mitigating neuroinflammation in an in vivo LPS-induced model, 7dr i establishes itself as a promising antineuroinflammatory agent.