AXL1717 is an orally active and highly selective insulin-like growth factor-1 receptor (IGF-1R) inhibitor with an IC50 value of 1nM[1]. IGF-1R is a transmembrane tyrosine kinase receptor overexpressed in various human cancers, playing a key role in promoting tumor cell proliferation, inhibiting apoptosis, and enhancing invasive and metastatic capabilities[2,3]. AXL1717 is commonly used in research related to the IGF-1R signaling pathway and various solid tumors such as malignant astrocytomas and non-small cell lung cancer[4,5].
In vitro, AXL1717 (0.2μM) combined with baicalein (BA) (20μM) treatment for 24h in lipopolysaccharide (LPS)-induced BV2 microglial cells significantly enhanced the inhibitory effect of BA on the expression of inflammatory factors IL-1β, IL-6, and TNF-α[6]. AXL1717 (10μM) treatment for 48h in high glucose (25mM)-induced human lung cancer A549 cells significantly inhibited high glucose environment-induced cell proliferation and suppressed cell migration ability[7].
In vivo, AXL1717 (0.15mg/day; i.p.) combined with BA (80mg/kg; p.o.) treatment for 30 days in a pilocarpine-induced epileptic rat model significantly prolonged survival time and reduced seizure frequency, duration, and Racine scores[6]. AXL1717 (40mg/kg; twice daily; i.p.) administered starting 2h before optic nerve crush surgery for 7 days in CD11b knockout (ltgam-/-) mice significantly reduced the area labeled by cholera toxin subunit B (CTB) in the optic nerve, reversing the axonal protective effects brought about by CD11b knockout[8].
References:
[1] EKMAN S, FRÖDIN J E, HARMENBERG J, et al. Clinical phase I study with an insulin-like growth factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma[J]. Acta Oncologica, 2011, 50(3): 441-447.
[2] JIN M, WANG J, BUCK E, et al. Small-molecule ATP-competitive dual IGF-1R and insulin receptor inhibitors: structural insights, chemical diversity and molecular evolution[J]. Future Medicinal Chemistry, 2012, 4(3): 315-328.
[3] WANG P, MAK V C, CHEUNG L W. Drugging IGF-1R in cancer: New insights and emerging opportunities[J]. Genes & Diseases, 2023, 10(1): 199-211.
[4] AIKEN R, AXELSON M, HARMENBERG J, et al. Phase I clinical trial of AXL1717 for treatment of relapsed malignant astrocytomas: Analysis of dose and response[J]. Oncotarget, 2017, 8(46): 81501.
[5] BERGQVIST M, HOLGERSSON G, BONDARENKO I, et al. Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer[J]. Acta Oncologica, 2017, 56(3): 441-447.
[6] FU P, YUAN Q, SUN Y, et al. Baicalein ameliorates epilepsy symptoms in a pilocarpine-induced rat model by regulation of IGF1R[J]. Neurochemical Research, 2020, 45(12): 3021-3033.
[7] FEI J, XIAO C, YANG M, et al. Inhibition of SNCG suppresses the proliferation of lung cancer cells induced by high glucose[J]. Molecular Medicine Reports, 2021, 23(2): 138.
[8] ZHOU J, LIN S, HU Q, et al. Microglial CD11b knockout contributes to axonal debris clearance and axonal degradation attenuation via IGF-1 after acute optic nerve injury[J]. Investigative Ophthalmology & Visual Science, 2023, 64(5): 7.
AXL1717是一种具有口服活性和高效选择性的胰岛素样生长因子1受体（IGF-1R）抑制剂，IC50值为1nM[1]。IGF-1R是一种在多种人类癌症中过表达的跨膜酪氨酸激酶受体，在促进肿瘤细胞增殖、抑制凋亡和增强侵袭转移能力中起关键作用[2,3]。AXL1717通常用于IGF-1R相关信号通路及恶性星形细胞瘤和非小细胞肺癌等多种实体瘤的研究[4,5]。
在体外，AXL1717（0.2μM）与黄芩素BA（20μM）联合处理经脂多糖（LPS）诱导的BV2小胶质细胞24h，显著增强了BA对炎症因子IL-1β、IL-6和TNF-α表达的抑制作用[6]。AXL1717（10μM）处理高糖（25mM）诱导的人肺癌A549细胞48h，显著抑制了高糖环境诱导的细胞增殖，并抑制了细胞的迁移能力[7]。
在体内，AXL1717（0.15mg/day; i.p.）联合BA（80mg/kg; p.o.）治疗毛果芸香碱诱导的癫痫大鼠模型30天，显著延长了生存时间，并降低了癫痫发作频率、持续时间和Racine评分[6]。AXL1717（40mg/kg; twice daily; i.p.）从视神经压迫手术前2h开始处理CD11b基因敲除（ltgam-/-）小鼠7天，显著降低了视神经中霍乱毒素亚基B（CTB）标记的面积，逆转了CD11b敲除所带来的轴突保护效应[8]。