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]
References:
[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>