Background
ALW-II-41-27 is an Eph family tyrosine kinase inhibitor with an IC50 of 11 nM to inhibit Eph2[1].
ALW-II-41-27(1μM;72 h) inhibited the proliferation of Erlotinib-resistant NSCLC cell lines and increased cell apoptosis. ALW-II-41-27 induced apoptosis was accompanied by an increase in caspase-3 and PARP and a decrease in the expression of anti-apoptotic proteins BCL-xL and MCL-1[3]. ALW-II-41-27(200, 600 or 1,000 nM ALW-II-41-27; 24, 48 or 72 h) inhibited cervical cancer (CC) cell proliferation, migration and invasion by blocking the RhoA/ROCK pathway[4]. ALW-II-41-27 inhibited pY772-EphA2 and EphA2-Y772A decreased the inhibitory effect of ALW-II-41-27 on NPC cell proliferation[6]. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1-G2 arrest[7].
ALW-II-41-27(15 mg/kg;14 days; i.p.) significantly inhibited growth of the erlotinib-resistant tumors[3]. Administration of ALW-II-41-27(15, 30 mg/kg;twice a day; i.p.)significantly inhibited H358 tumor growth in tumor-bearing mice. Histological analysis showed a significant increase in apoptosis in tumors treated with ALW-II-41-27 compared with those treated with NG-25 or the carrier, similar to the effect of genetic ablation of EPHA2[2]. ALW-II-41-27 (12.5, 25, 50, and 100 μg/kg; i.p.) decreased gastrointestinal motility and abdominal withdrawal reflex (AWR) scores, markedly reduced the levels of oxidative stress markers [4-hydroxy-2-nonenal (4-HNE), protein carbonyl, and 8-hydroxy-2-de-axyguanine (8-OHdG)] and proinflammatory cytokines (TNF-α, IL-6, IL-17, and ICAM-1), and remarkably increased the level of anti-inflammatory cytokine (IL-10) in serum and colon of Trichinella spiralis-infected mice[5].
参考文献:
[1]. Choi Y, Syeda F, et,al. Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4467-70. doi: 10.1016/j.bmcl.2009.05.029. Epub 2009 May 13. PMID: 19553108; PMCID: PMC2730633.
[2]. Amato KR, Wang S, et,al. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest. 2014 May;124(5):2037-49. doi: 10.1172/JCI72522. Epub 2014 Apr 8. PMID: 24713656; PMCID: PMC4001547.
[3]. Amato KR, Wang S, et,al. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res. 2016 Jan 15;76(2):305-18. doi: 10.1158/0008-5472.CAN-15-0717. Epub 2016 Jan 7. PMID: 26744526; PMCID: PMC4715957.
[4]. Li X, Li D, et,al.ALW-II-41-27, an EphA2 inhibitor, inhibits proliferation, migration and invasion of cervical cancer cells via inhibition of the RhoA/ROCK pathway. Oncol Lett. 2022 Apr;23(4):129. doi: 10.3892/ol.2022.13249. Epub 2022 Feb 18. PMID: 35251349; PMCID: PMC8895465.
[5]. Zeng L, Li K, et,al.A Novel EphA2 Inhibitor Exerts Beneficial Effects in PI-IBS in Vivo and in Vitro Models via Nrf2 and NF-κB Signaling Pathways. Front Pharmacol. 2018 Mar 27;9:272. doi: 10.3389/fphar.2018.00272. PMID: 29662452; PMCID: PMC5890185.
[6]. Xiang YP, Xiao T, et,al. Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway. Cell Death Dis. 2020 Aug 27;11(8):709. doi: 10.1038/s41419-020-02831-0. PMID: 32848131; PMCID: PMC7449971.
[7]. Martini G, Cardone C, et,al. EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer. Mol Cancer Ther. 2019 Apr;18(4):845-855. doi: 10.1158/1535-7163.MCT-18-0539. Epub 2019 Mar 1. PMID: 30824612.
ALW-II-41-27 是一种 Eph 家族酪氨酸激酶抑制剂，抑制 Eph2[1] 的 IC50 为 11 nM。
ALW-II-41-27(1μM;72 h) 抑制厄洛替尼耐药 NSCLC 细胞系的增殖并增加细胞凋亡。 ALW-II-41-27诱导的细胞凋亡伴随着caspase-3和PARP的增加以及抗凋亡蛋白BCL-xL和MCL-1[3]表达的降低。 ALW-II-41-27（200、600 或 1,000 nM ALW-II-41-27；24、48 或 72 小时）通过阻断 RhoA/ROCK 通路抑制宫颈癌 (CC) 细胞增殖、迁移和侵袭[4]。 ALW-II-41-27抑制pY772-EphA2，EphA2-Y772A降低ALW-II-41-27对NPC细胞增殖的抑制作用[6]。 ALW-II-41-27 加西妥昔单抗的联合治疗恢复了对西妥昔单抗的原发性和获得性耐药性，导致细胞生长抑制，诱导细胞凋亡和细胞周期 G1-G2 停滞[7]。
ALW-II-41-27（15 mg/kg；14 天；i.p.）显着抑制厄洛替尼耐药肿瘤的生长[3]。施用 ALW-II-41-27（15、30 mg/kg；每天两次；腹腔注射）显着抑制荷瘤小鼠中的 H358 肿瘤生长。组织学分析显示，与用 NG-25 或载体处理的肿瘤相比，用 ALW-II-41-27 处理的肿瘤细胞凋亡显着增加，类似于 EPHA2 基因消融的效果[2] . ALW-II-41-27（12.5、25、50 和 100 μg/kg；腹腔注射）降低胃肠动力和腹部退缩反射 (AWR) 评分，显着降低氧化应激标志物 [4-羟基-2-壬醛] 的水平(4-HNE)、蛋白质羰基和 8-羟基-2-脱氧鸟嘌呤 (8-OHdG)] 和促炎细胞因子（TNF-α、IL-6、IL-17 和 ICAM-1），并显着增加旋毛虫感染小鼠血清和结肠抗炎细胞因子（IL-10）水平的变化[5]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Non-small cell lung cancer (NSCLC) PC-9/ER, PC-9/ERC15, PC-9/ERC16 cell lines
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Preparation Method
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Four cell lines with acquired resistance to erlotinib were treated with ALW-II-41-27, NG-25, erlotinib, or DMSO for 72 hours, and cell viability was assessed by the MTT assay.
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Reaction Conditions
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1 μM;72 h
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Applications
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1 μM ALW-II-41-27 inhibited the proliferation of Erlotinib-resistant NSCLC cell lines and increased cell apoptosis. ALW-II-41-27 induced apoptosis was accompanied by an increase in caspase-3 and PARP and a decrease in the expression of anti-apoptotic proteins BCL-xL and MCL-1.
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| Animal experiment [2]: |
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Animal models
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6-week-old athymic nude mice
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Preparation Method
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HCC827/ER or PC-9/ERC16 cells were injected with Matrigel into the hind flanks of 6-week-old athymic nude mice. Mice were randomized by body weight and tumor volume into treatment groups to receive 15 mg/kg of either erlotinib, ALW-II-41-27, or the vehicle alone twice daily via intraperitoneal injection.
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Dosage form
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15 mg/kg;14 days; i.p.
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Applications
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After 14 days of the treatment regimen, ALW-II-41-27 significantly inhibited growth of the erlotinib-resistant tumors.
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参考文献:
[1]. Amato KR, Wang S, et,al. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res. 2016 Jan 15;76(2):305-18. doi: 10.1158/0008-5472.CAN-15-0717. Epub 2016 Jan 7. PMID: 26744526; PMCID: PMC4715957.
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