Pexidartinib (PLX3397)

Pexidartinib (PLX3397) is a potent, orally active, selective, and ATP-competitive CSF1R and c-Kit inhibitor, with IC₅₀ values of 0.02μM and 0.01μM, respectively^[1]. Pexidartinib stabilizes CSF1R in the auto-inhibited state by interacting with the CSF1R juxta-membrane region, resulting in inactivation of the kinase domain and prevention of CSF1 and ATP binding, which restrains the switch from a monocytic to macrophage phenotype^[2]. Pexidartinib has been widely used in cancer research to eliminate AKT phosphorylation induced by FLT3-L in vitro stimulation and to inhibit the growth of various tumor cells^[3].

In vitro, Pexidartinib treatment for 48 hours significantly inhibited the proliferation of A549 and Beas-2B cells, with IC₅₀ values of 1.3µM and 9.3µM, respectively^[4]. Treatment with 50μM Pexidartinib for 24 hours led to a decrease in ATP content in HepG2 cells, and induced endoplasmic reticulum stress and mitochondrial dysfunction^[5]. Treatment with 10μM Pexidartinib for 72 hours suppressed the expression of IL-8 and CCND1, as well as cell viability in 12Z cells^[6].

In vivo, Pexidartinib treatment via oral administration at a dose of 290mg/kg/day for 1 week ameliorated social isolation-induced depressive-like behaviors, promoted neurogenesis, and enhanced synaptic plasticity in mice^[7]. Oral administration of Pexidartinib at a dose of 75mg/kg every three days for 15 days inhibited the growth of adriamycin-resistant MCF-7 xenograft tumors and induced apoptosis in tumor tissues in nude mice^[8].

References:

[1] Lamb Y N. Pexidartinib: First Approval: YN Lamb[J]. Drugs, 2019, 79(16): 1805-1812.

[2] Benner B, Good L, Quiroga D, et al. Pexidartinib, a novel small molecule CSF-1R inhibitor in use for tenosynovial giant cell tumor: a systematic review of pre-clinical and clinical development[J]. Drug design, development and therapy, 2020: 1693-1704.

[3] Voissière A, Gomez-Roca C, Chabaud S, et al. The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers[J]. Science translational medicine, 2024, 16(731): eadd1834.

[4] Hacıosmanoğlu‐Aldoğan E, Lama D, Yetke H İ, et al. Necroptotic suppression of lung cancer cell proliferation and migration: a comprehensive in vitro and in silico study to determine new molecular targets for pexidartinib[J]. Cell Biochemistry and Function, 2025, 43(3): e70068.

[5] Chen S, Li Y, Li X, et al. Mechanistic study of pexidartinib-induced toxicity in human hepatic cells[J]. Chemico-biological interactions, 2025, 419: 111641.

[6] Dunn T N, Cope D I, Tang S, et al. Inhibition of CSF1R and KIT with pexidartinib reduces inflammatory signaling and cell viability in endometriosis[J]. Endocrinology, 2024, 165(4): bqae003.

[7] Wang L, Wang X, Deng L, et al. Pexidartinib (PLX3397) through restoring hippocampal synaptic plasticity ameliorates social isolation-induced mood disorders[J]. International Immunopharmacology, 2022, 113: 109436.

[8] Peng R, Zhan Y, Cheng Z, et al. Targeting the MAPK/ERK Signaling Pathway: Mechanistic Analysis of Pexidartinib in Overcoming Adriamycin Resistance in Breast Cancer[J]. Experimental Cell Research, 2026: 115127.