PLX5622 | Highly selective CSF1R inhibitor

PLX5622 (1303420-67-8) is a highly selective (>20 fold over KIT and FLT3, >60 fold over 200 other kinases) and brain-penetrant inhibitor of colony-stimulating factor 1 receptor (CSF1R; IC₅₀ = 16 nM).¹ It prevented plaque formation in 5xFAD¹ and 3xTg² mouse models of Alzheimer’s disease via elimination of microglia in a CSF1R-dependent manner.  PLX5622 showed efficacy in a mouse neuropathic pain model via reduction of CD86+ macrophages resulting in reduced expression of pro-inflammatory cytokines.³ It also was able to ameliorate peripheral neuropathy in aging mice.⁴ PLX5622 displayed neuroprotective effects during the chronic phase of a traumatic brain injury mouse model.5  PLX5622 has also been shown to affect myeloid and lymphoid compartments, indicating that its affects are not limited to microglia and include peripheral immune cells.⁶

References/Citations:

1. Spangenberg et al. (2019) Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model; Nat. Commun. 10 3758
2. Dagher et al. (2015) Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice; J.  Neuroinflammation 12 139
3. Lee et al. (2018) Targeting macrophage and microglia activation with colony stimulating factor 1 receptor inhibitor is an effective strategy to treat injury-triggered neuropathic pain; Mol.  Pain 14 1
4. Yaun et al. (2018) Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.; J.  Neurosci. 38 4610
5. Henry et al. (2020) Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits.; J.  Neurosci. 40 2960
6. Lei et al. (2020) CSF1R inhibition by a small-molecule inhibitor is not microglia specific; affecting hematopoiesis and the function of macrophages.; Proc.  Natl. Acad. Sci USA 117 23336