PLX5622 hemifumarate

PLX5622 hemifumarate is the fumarate salt form of PLX5622 (CAS 1303420‑67‑8, Cat. No. B8575). PLX5622 is a highly specific, orally bioavailable tyrosine kinase inhibitor targeting the colony-stimulating factor 1 receptor (CSF‑1R). It exhibits potent inhibitory activity against CSF‑1R (IC₅₀ ≈ 0.016 μM), while its inhibitory effects on other kinases such as c‑kit are markedly weaker than those of the related compound PLX3397 (CAS 1029044‑16‑3, Cat. No. B5854). PLX5622 efficiently penetrates the blood–brain barrier.

At the functional level, PLX5622 can deplete up to 99% of microglia in rodent models and selectively depletes interstitial macrophages in the lung as well as Ly6C^low patrolling monocytes within the central nervous system. In models of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, it reduces neuroinflammation and neurodegeneration. In a cryptococcal pulmonary infection model, PLX5622 lowers fungal burden and limits dissemination to the central nervous system. In contrast, microglial depletion by PLX5622 exacerbates optic nerve damage in glaucoma models.

Mechanistically, PLX5622 exerts its effects by competitively binding to the intracellular tyrosine kinase domain of CSF‑1R, thereby blocking CSF‑1/IL‑34–mediated downstream signaling pathways. This inhibition suppresses the proliferation, differentiation, and survival of microglia, macrophages, and other myeloid cells that depend on this pathway, ultimately modulating inflammatory responses and associated cellular functions.

References:

[1] Diemler CA, MacLean M, Heuer SE, Hewes AA, Marola OJ, Libby RT, Howell GR. Microglia depletion leads to increased susceptibility to ocular hypertension-dependent glaucoma. Front Aging Neurosci. 2024 Jul 2;16:1396443. doi: 10.3389/fnagi.2024.1396443. PMID: 39015474; PMCID: PMC11250491.

[2] Mohamed SH, Vanhoffelen E, Shun Fu M, Hei Lau P, Hain S, Seldeslachts L, Cosway E, Anderson G, McCulloch L, Vande Velde G, Drummond RA. CSF1R inhibition by PLX5622 reduces pulmonary fungal infection by depleting MHCIIhi interstitial lung macrophages. Mucosal Immunol. 2024 Dec;17(6):1256-1272. doi: 10.1016/j.mucimm.2024.08.007. Epub 2024 Aug 20. PMID: 39168451.

[3] Guenoun D, Blaise N, Sellam A, Roupret-Serzec J, Jacquens A, Steenwinckel JV, Gressens P, Bokobza C. Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF-1R. Glia. 2025 Apr;73(4):686-700. doi: 10.1002/glia.24664. Epub 2024 Dec 24. PMID: 39719687; PMCID: PMC11845850.