Targeting the CSF-1/CSF-1R Axis: Exploring the Potential of CSF1R Inhibitors in Neurodegenerative Diseases
- Authors
- Baek, Jihyun; Jun, Joonhong; Kim, Hyejin; Bae, Hyunah; Park, Haebeen; Cho, Hyunwook; Han, Songhee; Shin, Ho Chul; Hah, Jung-Mi
- Issue Date
- Mar-2024
- Publisher
- American Chemical Society
- Citation
- Journal of Medicinal Chemistry, v.67, no.7, pp 1 - 22
- Pages
- 22
- Indexed
- SCIE
SCOPUS
- Journal Title
- Journal of Medicinal Chemistry
- Volume
- 67
- Number
- 7
- Start Page
- 1
- End Page
- 22
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/118726
- DOI
- 10.1021/acs.jmedchem.3c02366
- ISSN
- 0022-2623
1520-4804
- 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 & horbar;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.
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