Pexidartinib(PLX3397) is an orally administered small molecule tyrosine kinase inhibitor with potent selective activity against the colony-stimulating factor 1(CSF1) receptor(IC50=20nM), KIT proto-oncogene receptor tyrosine kinase(KIT)(IC50 =10nM) and FMS-like tyrosine kinase 3[1,2]
Pexidartinib was a stronger KIT inhibitor than imatinib in vitro. Compared pexidartinib and imatinib in vitro against 2 human GIST cell lines that harbor an imatinib-sensitive, activating KIT exon 11 mutation. Indeed, pexidartinib decreased viability in both cell lines with two-fold greater potency than imatinib, with an IC50 of 8-18 nM versus 42 nM(p<0.05). At concentrations similar to the IC50 of each drug, i.e., 10 and 40 nM, PLX3397 also decreased phospho-KIT relative to total KIT more effectively than imatinib in vitro[3]
Pexidartinib is effective in reducing adipose tissue macrophage levels of chow and high fat diet mice without affecting total myeloid cell levels[4]. A research found pexidartinib was well-tolerated in non-human primates(NHPs), with no Grade 3 or Grade 4 toxicities. Pexidartinib has limited CSF penetrance in NHPs following oral administration of a single dose[5]
Pexidartinib received its first approval on 2 August 2019 in the USA for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery[2]
参考文献:
[1].Fujiwara T, Yakoub MA, Chandler A, et al. CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. Mol Cancer Ther. 2021;20(8):1388-1399.
[2].Lamb YN. Pexidartinib: First Approval [published correction appears in Drugs. 2020 Mar;80(4):447]. Drugs. 2019;79(16):1805-1812.
[3].Liu Y, Given KS, Dickson EL, et al. Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo. Exp Neurol. 2019;318:32-41.
[4].Merry TL, Brooks AES, Masson SW, et al. The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice. Int J Obes (Lond). 2020;44(1):245-253.
[5].Shankarappa PS, Peer CJ, Odabas A, et al. Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, pexidartinib. Cancer Chemother Pharmacol. 2020;85(5):1003-1007.
Pexidartinib(PLX3397) 是一种口服小分子酪氨酸激酶抑制剂，对集落刺激因子 1(CSF1) 受体 (IC50=20nM)、KIT 原癌基因受体酪氨酸激酶 (KIT)(IC50 = 10nM) 和类 FMS 酪氨酸激酶 3[1,2]
Pexidartinib 在体外是一种比伊马替尼更强的 KIT 抑制剂。将 pexidartinib 和伊马替尼在体外与 2 个人类 GIST 细胞系进行比较，这些细胞系具有伊马替尼敏感的激活 KIT 外显子 11 突变。事实上，pexidartinib 降低了两种细胞系的活力，效力是伊马替尼的两倍，IC50 分别为 8-18 nM 和 42 nM(p&<0.05)。在与每种药物的 IC50 相似的浓度下，即 10 和 40 nM，PLX3397 在体外也比伊马替尼更有效地降低磷酸化 KIT 相对于总 KIT[3]
Pexidartinib 可有效降低食物和高脂肪饮食小鼠的脂肪组织巨噬细胞水平，而不影响总骨髓细胞水平[4]。一项研究发现，pexidartinib 在非人类灵长类动物 (NHP) 中具有良好的耐受性，没有 3 级或 4 级毒性。 Pexidartinib 在 NHPs 中口服单剂量后 CSF 外显率有限[5]
Pexidartinib 于 2019 年 8 月 2 日在美国首次获得批准，用于治疗伴有严重发病率或功能受限且无法通过手术改善的症状性 TGCT 成年患者[2]/ p>
| Cell experiment [1]: | |
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Cell lines |
LM8(RCB1450)、NFSa(RCB0282)、KUM5(RCB2322)、LAG(RCB2758) |
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Reaction Conditions |
a 10mmol/L stock of pexidartinib was formulated in dimethyl sulfoxide (DMSO) |
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Applications |
In vitro administration of pexidartinib suppressed pERK1/2 stimulation by CSF1 or TCM. CSF1R blockade in the in vitro TAM model resulted in reduced viability and chemotaxis of macrophages and polarization from M2-like to a more M1-like phenotype |
| Animal experiment [2]: | |
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Animal models |
Two-month-old 5XFAD mice |
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Preparation Method |
Treated two-month-old 5XFAD mice with pexidartinib, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, analyse the amount of intraneuronal amyloid and neuritic plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze |
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Dosage form |
290mg/kg formulated in standard chow，3 month |
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Applications |
Early long-term treatment with the CSF1R inhibitor, pexidartinib significantly reduced intraneuronal amyloid, neuritic plaque formation, a reduced amount of toxic prefibrillar oligomers and improved cognitive function in particular associative learning in the contextual fear conditioning of 5XFAD mice. |
| Clinical trial [3]: | |
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human subjects |
Eligible patients were 18 years old or older and have a histologically confirmed TGCT that was both unresectable and symptomatic |
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Preparation Method |
The pooled analysis encompassed 3 groups of pexidartinib-treated patients with TGCT: 1) patients from a phase 1 extension study, 2) patients from ENLIVEN who were randomized to pexidartinib at 1000mg/d for 2 weeks and then 800mg/d, and 3) crossover patients from ENLIVEN receiving pexidartinib at 800mg/d. |
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Applications |
One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). |
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参考文献: [1].Fujiwara T, Yakoub MA, Chandler A, et al. CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. Mol Cancer Ther. 2021;20(8):1388-1399. [2].Sosna J, Philipp S, Albay R 3rd, et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener. 2018;13(1):11. Published 2018 Mar 1. [3].Gelderblom H, Wagner AJ, Tap WD, et al. Long-term outcomes of pexidartinib in tenosynovial giant cell tumors. Cancer. 2021;127(6):884-893. |
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