AF38469 is an orally active Sortilin (SORT1; IC₅₀=330nM) receptor inhibitor[1-2]. AF38469 possesses antioxidant functions. AF38469 can be used in research related to neurodegenerative diseases and cancer[3-4].
In vitro, pancreatic cancer cells (PANC-1, MIA PaCa-2, PaCa-44) were treated with AF38469 (10μM) for 6-24 hours. AF38469 inhibited cell adhesion and invasion, reduced cell migration capacity, and decreased the phosphorylation of focal adhesion kinase (FAK) at Tyr925[5]. Human primary Müller cells and rat Müller cells (rMC-1) cultured under 25mM high glucose conditions were treated with AF38469 (20μM) for 24 hours. AF38469 significantly reduced the protein levels of sortilin, NOD-like receptor protein 3 (NLRP3), tumor necrosis factor α (TNFα), P75 neurotrophin receptor (P75NTR), lysosomal-associated membrane protein 2 (LAMP2), and cleaved caspase 3[6].
In vivo, mice bearing MDA-MB 231-luc xenografts and receiving repetitive GRN A injections were treated with AF38469 (5-10μg/day/mouse) via drinking water for 3 weeks. AF38469 significantly reduced GRN A-induced lung metastasis and prevented cancer cell infiltration of the skin[7]. Male C57BL/6J mice on a Western diet starting at 12 weeks of age for 8 weeks were treated with AF38469 (approximately 4mg/kg/day, orally mixed in feed). AF38469 significantly lowered plasma cholesterol levels and reduced hepatic VLDL secretion and pro-inflammatory cytokine expression[8].
References:
[1] Pearson AC, Miller JS, Jensen HJ, et al. Neurotensin Regulates Primate Ovulation Via Multiple Neurotensin Receptors. Endocrinology. 2025 Mar 24;166(5):bqaf041.
[2] Li C, Jiang N, Liu Y, et al. Toxoplasma sortilin interacts with secretory proteins and it is critical for parasite proliferation. Parasit Vectors. 2024 Mar 4;17(1):105.
[3] Yang W, Wu PF, Ma JX, et al. Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3β/β-catenin/twist pathway. Cell Death Dis. 2019 Feb 27;10(3):208.
[4] Schrøder TJ, Christensen S, Lindberg S, et al. The identification of AF38469: an orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin. Bioorg Med Chem Lett. 2014 Jan 1;24(1):177-80.
[5] Gao F, Griffin N, Faulkner S, et al. The Membrane Protein Sortilin Can Be Targeted to Inhibit Pancreatic Cancer Cell Invasion. Am J Pathol. 2020 Sep;190(9):1931-1942.
[6] Liu L, Jiang Y, Steinle JJ. Inhibition of sortilin reduces neuronal and vascular damage after ischemia/reperfusion through reduced inflammatory and autophagy actions in retinal Müller cells. Mol Vis. 2025 Oct 3;31:359-366.
[7] Rhost S, Hughes É, Harrison H, et al. Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion. Breast Cancer Res. 2018 Nov 20;20(1):137.
[8] Chen C, Li J, Matye DJ, et al. Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice. J Lipid Res. 2019 Mar;60(3):539-549.
AF38469是一种具有口服活性的Sortilin（SORT1；IC50=330nM）受体抑制剂[1-2]。AF38469具有抗氧化功能。AF38469可用于神经退行性疾病和癌症的相关研究[3-4]。
在体外，AF38469（10μM）处理胰腺癌细胞（PANC-1，MIA PaCa-2，PaCa-44）6-24小时。AF38469可抑制细胞的粘附与侵袭，并降低细胞迁移能力，同时减少黏着斑激酶（FAK）在Tyr925位点的磷酸化[5]。AF38469（20μM）处理在25mM高葡萄糖条件下培养的人原代Müller细胞和大鼠Müller细胞（rMC-1）24小时。AF38469显著降低了sortilin、NOD样受体蛋白3（NLRP3）、肿瘤坏死因子α（TNFα）、P75神经营养因子受体（P75NTR）、溶酶体相关膜蛋白2（LAMP2）和cleaved caspase 3的蛋白水平[6]。
在体内，AF38469（5-10μg/天/只小鼠）通过饮水给药处理携带MDA-MB 231-luc异种移植瘤并接受GRN A重复注射的小鼠。持续3周。AF38469显著减少了GRN A诱导的肺转移，并阻止了癌细胞对皮肤的浸润[7]。AF38469（每日约4mg/kg，混合于饲料中口服给药）用于处理12周龄开始、持续8周的西方饮食喂养的雄性C57BL/6J小鼠。AF38469显著降低了血浆胆固醇水平，并减少了肝脏VLDL分泌和促炎细胞因子的表达[8]。