FLI-06 is a Notch signaling inhibitor (EC50 = 2.3µM) that acts upstream of α-secretase and β-secretase cleavage. FLI-06 disrupts intracellular trafficking and processing of the Notch signaling pathway, inhibiting general secretion at a stage prior to exiting the endoplasmic reticulum (ER) and transforming the ER morphology from tubules to lamellae. FLI-06 for the treatment of cancer and neurodegenerative diseases [1-4].
In ECa109 and EC9706 cells, FLI-06 (0, 2, 4, 8, 12, 14, 16, 18 and 20μM, 48h) blocked proliferation, induced apoptosis and G1 phase arrest of ESCC cells in a dose-dependent manner [5]. In CAL-27 and TCA-8113 cells, FLI-06 (0, 3, and 10μM, 48h) could block tongue cancer cell growth in a concentration-dependent manner [6]. In HNSCC cells, FLI-06 (10μM, 24h) affecting cells proliferation, growth and formation of HNSCC organoids, and effective inhibits Notch signaling in HNSCC cells [7]. In hepatocytes, FLI-06 (50μM, 24h) treatment abolished the Jagged-1-induced upregulation of NICD, p-Akt, HIF-1α, and cyclin E1 [8]. In mouse hippocampal NSCs, treatment with FLI-06 (20μM, 24h) inhibited the effects of CCN3 or shCCN3 on hippocampal NSC proliferation and neuronal differentiation [9]. In H1975 cells, ZFR-promoted migration and invasion in H1975 cells was abolished by FLI-06 (100nM, 1h) [10].
In CAL-27 xenograft mouse models, the tumor volume and tumor weight of the FLI-06 (40mg/kg, ip, 18d) treatment group were decreased compared with the control group [6]. In SD mouse, FLI-06 (3mg/kg, ip, 28d) inhibits liver regeneration after partial hepatectomy [11].
References:
[1]. Krämer A, Mentrup T, Kleizen B, et al. Small molecules intercept Notch signaling and the early secretory pathway. Nature chemical biology. 2013 Nov; 9(11): 731-738.
[2]. Yonemura Y, Li X, Müller K, et al. Inhibition of cargo export at ER exit sites and the trans-Golgi network by the secretion inhibitor FLI-06. Journal of Cell Science. 2016 Oct 15; 129(20): 3868-3877.
[3]. Gómez-Galeno JE, Hurtado C, Cheng J, et al. b-Annulated 1, 4-dihydropyridines as Notch inhibitors. Bioorganic & medicinal chemistry letters. 2018 Nov 1; 28(20): 3363-3367.
[4]. Yonemura Y, Li X, Müller K, et al. Inhibition of cargo export at ER exit sites and the trans-Golgi network by the secretion inhibitor FLI-06. Journal of Cell Science. 2016 Oct 15; 129(20): 3868-3877.
[5]. Lu Z, Ren Y, Zhang M, et al. FLI-06 suppresses proliferation, induces apoptosis and cell cycle arrest by targeting LSD1 and Notch pathway in esophageal squamous cell carcinoma cells. Biomedicine & Pharmacotherapy. 2018 Nov 1; 107: 1370-1376.
[6]. Gan RH, Lin LS, Xie J, et al. FLI-06 intercepts notch signaling and suppresses the proliferation and self-renewal of tongue cancer cells. OncoTargets and therapy. 2019 Sep 18: 7663-7674.
[7]. Czerwonka A, Kałafut J, Wang S, et al. The Notch inhibitor, FLI-06, increases the chemosensitivity of head and neck Squamous cell carcinoma cells to taxanes-based treatment. Biomedicine & Pharmacotherapy. 2024 Aug 1; 177: 116822.
[8]. Zhang F, Zhang J, Li X, et al. Notch signaling pathway regulates cell cycle in proliferating hepatocytes involved in liver regeneration. Journal of gastroenterology and hepatology. 2018 Aug; 33(8): 1538-1547.
[9]. Luan Y, Zhang H, Ma K, et al. CCN3/NOV regulates proliferation and neuronal differentiation in mouse hippocampal neural stem cells via the activation of the notch/PTEN/AKT pathway. International Journal of Molecular Sciences. 2023 Jun 19; 24(12): 10324.
[10]. Zhang H, Zhang CF, Chen R. Zinc finger RNA-binding protein promotes non-small-cell carcinoma growth and tumor metastasis by targeting the Notch signaling pathway. American Journal of Cancer Research. 2017 Sep 1; 7(9): 1804.
[11]. Li Y, Xu Y, Wang R, et al. Expression of Notch–Hif-1α signaling pathway in liver regeneration of rats. Journal of International Medical Research. 2020 Sep; 48(9): 0300060520943790.
FLI-06是一种Notch信号抑制剂(EC50 = 2.3µM)，作用于α-分泌酶和β-分泌酶裂解的上游。FLI-06可阻断Notch信号通路的细胞内运输和加工，抑制细胞在离开内质网（ER）之前的分泌，并使内质网形态从小管转变为片层。FLI-06用于治疗癌症和神经退行性疾病 [1-4]。
在ECa109和EC9706细胞中，FLI-06（0、2、4、8、12、14、16、18和20μM，48h）以剂量依赖性方式抑制ESCC细胞增殖，诱导细胞凋亡并使其进入G1期 [5]。在CAL-27和TCA-8113细胞中，FLI-06（0、3和10μM，48h）能够浓度依赖性地抑制舌癌细胞的生长 [6]。在HNSCC细胞中，FLI-06（10μM，24h）影响细胞增殖、生长和HNSCC类器官的形成，并有效抑制HNSCC细胞中的Notch信号传导 [7]。在肝细胞中，FLI-06（50μM，24h）处理消除了Jagged-1诱导的NICD、p-Akt、HIF-1α和细胞周期蛋白E1的上调 [8]。在小鼠海马NSC中，FLI-06（20μM，24h）处理可抑制CCN3或shCCN3对海马NSC增殖和神经元分化的影响 [9]。在H1975细胞中，FLI-06（100nM，1h）可消除ZFR促进的H1975细胞迁移和侵袭 [10]。
在CAL-27异种移植小鼠模型中，FLI-06（40mg/kg，ip，18d）治疗组的肿瘤体积和肿瘤重量均较对照组降低 [6]。在SD小鼠中，FLI-06（3mg/kg，ip，28d）可抑制部分肝切除术后的肝脏再生 [11]。