PLX5622 is a highly selective brain-penetrant CSF1R inhibitor allowing for extended and specific microglial elimination, preceding and during pathology development.
icroglia are the resident immune cells in the central nervous system. The Colony-stimulating factor-1 receptor (CSF-1R) is expressed by microglia, macrophages and osteoclasts, and is required for their proliferation, differentiation, and survival. PLX5622 is an orally bioavailable, brain-penetrant and highly selective CSF-1R inhibitor with IC50 < 10 nM, showing > 20-fold selectivity over KIT and FLT3[1]. Oral PLX5622 (1200 ppM) treatment in 5xFAD mice model of Alzheimer’s disease with increased numbers of microglia/myeloid cells and masses of enlarged, plaque-associated cells throughout the brain led to almost complete microglial elimination (97–100% reduction), even with 24 weeks of treatment[1]. Approximately 99% of microglia were eliminated by embryonic day 15.5 (E15.5) and numbers of apoptotic cells accumulating throughout the developing hypothalamus were elevated after pregnant dams were placed on a PLX5622 diet starting at E3.5[2].
作用机制
PLX5622 is anchored to the active site of CSF1R by 3 hydrogen bonds. 7-Azaindole of PLX5622 forms two hydrogen bonds with the hinge region of CSF1R whereas the central pyridine ring forms a hydrogen bond with the main chain amino group of Phe796.
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