PLX5622
[CAS# 1303420-67-8]

Identification

• Classification: Biochemical >> Inhibitor >> PI3K/Akt/mTOR inhibitor (PI3K/Akt/mTOR) >> S6 Kinase inhibitor
• Name: PLX5622
• Synonyms: 6-fluoro-N-[(5-fluoro-2-methoxypyridin-3-yl)methyl]-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyridin-2-amine
• Molecular Formula: C₂₁H₁₉F₂N₅O
• Molecular Weight: 395.41
• CAS Registry Number: 1303420-67-8
• SMILES: CC1=CC2=C(NC=C2CC3=C(N=C(C=C3)NCC4=C(N=CC(=C4)F)OC)F)N=C1

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Index of refraction: 1.666 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P280-P301+P312-P302+P352-P305+P351+P338

Discovory and Applicatios

PLX5622 is a small-molecule inhibitor of colony-stimulating factor 1 receptor (CSF1R), a receptor tyrosine kinase expressed predominantly on cells of the mononuclear phagocyte system, including microglia, macrophages, and monocytes. CSF1R is a key regulator of the development, survival, and function of these cells. PLX5622 was developed as part of a series of selective CSF1R inhibitors designed to modulate immune activity in various disease contexts by targeting myeloid-lineage cell populations. The compound was synthesized and optimized to provide high specificity for CSF1R over related kinases, enabling selective modulation of microglia in the central nervous system with minimal off-target effects.

The compound was first characterized in vitro using kinase inhibition assays, which confirmed its high potency against CSF1R and selectivity over kinases such as FLT3 and KIT. Cellular assays further demonstrated that PLX5622 effectively inhibits CSF1R phosphorylation and downstream signaling cascades involved in the proliferation and survival of macrophage-lineage cells. In microglial cultures, treatment with PLX5622 resulted in dose-dependent depletion of viable cells, indicating its functional ability to suppress CSF1R-dependent microglial survival mechanisms.

PLX5622 gained widespread use in neuroscience research due to its capacity to deplete microglia in vivo following oral administration. Rodent studies showed that inclusion of PLX5622 in the diet or drinking water could eliminate more than 90% of microglia within the brain within a few days, without causing overt neuronal toxicity or systemic immune deficiency. This feature made PLX5622 a valuable tool compound for investigating the physiological and pathological roles of microglia in neurodevelopment, synaptic plasticity, neuroinflammation, and neurodegeneration.

Applications of PLX5622 in animal models have included studies on Alzheimer's disease, Parkinson's disease, traumatic brain injury, multiple sclerosis, and retinal degeneration. In these models, microglial depletion using PLX5622 has been used to assess the contribution of microglia to disease progression, inflammation, synapse loss, and tissue remodeling. In some contexts, microglial elimination led to beneficial outcomes, such as reduced neuroinflammatory markers and improved behavioral performance. In other settings, microglia removal exacerbated disease features, highlighting the context-dependent role of these cells in central nervous system homeostasis and pathology.

Beyond neuroscience, PLX5622 has been utilized in models of cancer, fibrosis, and immune-related diseases to study the function of macrophages and other CSF1R-expressing cells. In tumor biology, PLX5622 has been used to deplete tumor-associated macrophages (TAMs), which often contribute to immunosuppression, angiogenesis, and metastasis. In fibrotic models, the compound has been employed to assess the role of macrophage subsets in fibrogenesis and tissue repair. These studies have helped delineate the diverse roles of CSF1R-positive cells across organ systems.

Pharmacokinetic analyses have shown that PLX5622 is orally bioavailable and penetrates the blood-brain barrier efficiently, maintaining effective concentrations in the brain with continuous dietary administration. The compound is well tolerated in rodents under typical experimental conditions. Reintroduction of normal diet leads to repopulation of microglia over time, allowing reversible modulation of microglial populations for longitudinal studies.

PLX5622 has not been approved for clinical use in humans and is primarily employed as a research tool in preclinical settings. Its utility has advanced understanding of myeloid cell biology and supported the development of CSF1R-targeted therapies for inflammatory, neurodegenerative, and neoplastic diseases. It remains a widely cited and experimentally validated compound in immunology and neuroscience research.

References

2015. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. Journal of Neuroinflammation, 12(1).
DOI: 10.1186/s12974-015-0366-9

2023. CXCR2-Blocking Has Context-Sensitive Effects on Rat Glioblastoma Cell Line Outgrowth (S635) in an Organotypic Rat Brain Slice Culture Depending on Microglia-Depletion (PLX5622) and Dexamethasone Treatment. International Journal of Molecular Sciences, 24(23).
DOI: 10.3390/ijms242316803

2024. Polarized macrophage functions are affected differentially after CSF-1R inhibition with PLX5622. European Journal of Pharmacology, 985.
DOI: 10.1016/j.ejphar.2024.177059