NT157 is a selective inhibitor of insulin receptor substrate-1/-2 (IRS-1/2)[1]. IRS-1/2 are important cytoplasmic adaptor proteins that mediate insulin and insulin-like growth factor 1 (IGF-1) signaling, playing critical roles in glucose metabolism, cell growth, and development[2]. NT157 exerts its effects by inducing apoptosis and disrupting key signaling pathways and is commonly used in drug research and development for various diseases, including melanoma, prostate cancer, and colorectal cancer[3,4].
In vitro, pretreatment of osteosarcoma MG-63 and U-2OS cells with NT157 (3μM) for 24h significantly inhibited cell migration ability, accompanied by downregulation of IRS-2 protein[5]. Treatment of H1299 and H460 cells with NT157 (3.2, 6.4, 12.5μM) for 7 days resulted in a dose-dependent and significant inhibition of colony formation ability; at the concentration of 12.5μM, the colony formation rates of H1299 and H460 cells decreased to 1.4% and 0.8% of the control group, respectively[6].
In vivo, NT157 (100mg/kg; twice daily) was administered via intraperitoneal injection for 4 weeks in a nude mouse model of lung metastasis of hepatocellular carcinoma established by tail vein injection of SMMC-7721 cells, significantly reducing the incidence of lung metastasis compared to the control group[7]. NT157 (70mg/kg; thrice weekly) was administered via intravenous injection for 4 weeks in mice subcutaneously inoculated with A375SM cells, 48h after the final dose, pY(705)Stat3 levels in tumor tissues were significantly reduced[4].
References:
[1] DE QUEIROZ G N, LIMA K, DE MIRANDA L B L, et al. NT157 exhibits antineoplastic effects by targeting IRS and STAT3/5 signaling in multiple myeloma[J]. Hematology, Transfusion and Cell Therapy, 2024, 46: S112-S121.
[2] RABIEE A, KRÜGER M, ARDENKJÆR-LARSEN J, et al. Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action[J]. Cellular Signalling, 2018, 47: 1-15.
[3] IBUKI N, GHAFFARI M, REUVENI H, et al. The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer[J]. Molecular Cancer Therapeutics, 2014, 13(12): 2827-2839.
[4] FLASHNER-ABRAMSON E, KLEIN S, MULLIN G, et al. Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling[J]. Oncogene, 2016, 35(20): 2675-2680.
[5] GAROFALO C, CAPRISTO M, MANCARELLA C, et al. Preclinical effectiveness of selective inhibitor of IRS-1/2 NT157 in osteosarcoma cell lines[J]. Frontiers in Endocrinology, 2015, 6: 74.
[6] DE MIRANDA L B L, LIMA K, COELHO-SILVA J L, et al. NT157 exerts antineoplastic activity by targeting JNK and AXL signaling in lung cancer cells[J]. Scientific Reports, 2022, 12(1): 17092.
[7] YU S Z, WANG Y, LV K J, et al. NT157 inhibits HCC migration via downregulating the STAT3/Jab1 signaling pathway[J]. Technology in Cancer Research & Treatment, 2021, 20: 15330338211027916.
NT157是一种具有选择性的胰岛素受体底物-1/-2（IRS-1/2）抑制剂[1]。IRS-1/2是重要的细胞质结合蛋白，介导胰岛素和胰岛素样生长因子1（IGF-1）信号传导，在葡萄糖代谢、细胞生长和发育中发挥关键作用[2]。NT157通过诱导细胞凋亡和破坏关键信号通路起作用，通常用于黑色素瘤、前列腺癌和结直肠癌等多种疾病药物的研究和开发[3,4]。
在体外，NT157（3μM）预处理肉骨瘤MG-63和U-2OS细胞24h，显著抑制了细胞的迁移能力，并伴随IRS-2蛋白的下调[5]。NT157（3.2, 6.4, 12.5μM）处理H1299和H460细胞7天，可剂量依赖性地显著抑制克隆形成能力，在12.5μM浓度下H1299和H460细胞的克隆形成率分别降至对照组的1.4%和0.8%[6]。
在体内，NT157（100mg/kg; twice daily）通过腹腔注射治疗经尾静脉注射SMMC-7721细胞构建的肝癌肺转移裸鼠模型4周，较对照可显著降低小鼠的肺转移发生率[7]。NT157（70mg/kg; thrice weekly）通过静脉注射治疗皮下接种A375SM细胞的小鼠4周，末次给药48h后肿瘤组织中pY(705)Stat3水平显著降低[4]。