Targeting the CSF-1/CSF-1R Axis: Exploring the Potential of CSF1R Inhibitors in Neurodegenerative Diseases

  • J Med Chem. 2024 Apr 11;67(7):5699-5720. doi: 10.1021/acs.jmedchem.3c02366.
Jihyun Baek  1 ,  Joonhong Jun  1 ,  Hyejin Kim  1 ,  Hyunah Bae  1 ,  Haebeen Park  1 ,  Hyunwook Cho  1 ,  Songhee Han  2 ,  Ho Chul Shin  2 ,  Jung-Mi Hah  1
Affiliations
  • 1. Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do 15588, Republic of Korea.
  • 2. Research Center, Whan In Pharmaceutical Co., Ltd., 11, Beobwon-ro 6-gil, Songpa-gu, Seoul 05855, Korea.
PMID: 38530425 DOI: 10.1021/acs.jmedchem.3c02366
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─7dri and 7dsi. 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 7dri for CSF-1R. Notably, 7dri 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, 7dri establishes itself as a promising antineuroinflammatory agent.

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