Amlexanox (AA673), a tricyclic amine carboxylic acid with oral activity, can effectively inhibit TANK-binding kinase 1 (TBK1) (IC50 = 0.8μM) and inhibitor-kappaB kinase epsilon (IKK-ɛ) (IC50 = 5.8μM)[1]. Amlexanox selectively inhibits G protein-coupled receptor kinase (GRK) 5 (IC50 =8.86μM), which can used as an anti-inflammatory and anti-allergic immunomodulator in various animal models[2].
In vitro, Amlexanox treatment for 72h significantly inhibited the proliferation of U87 cells and U251 cells, with IC50 values of 140μM and 120μM, respectively[3]. The treatment with Amlexanox (6μM) for 24 hours significantly reduced the expression of pro-inflammatory cytokines and chemokines in murine BV2 cells, and human HMC3 microglial cells induced by lipopolysaccharide (LPS) (100ng/ml)[4]. Treatment of PC3 cells with 5μM Amlexanox for 7 days resulted in upregulation of adhesion molecules (EpCAM, DSP, Claudin1, ZO1 and E-cadherin), and inhibition of mesenchymal genes and integrin α5[5].
In vivo, Amlexanox treatment via daily oral administration at a dose of 25mg/kg for 8 weeks prevented and reversed obesity caused by a high-fat diet in male C57BL/6 mice [6]. Treatment of Amlexanox (50mg/kg/day; p.o.)for 4 weeks decreased hepatic fibrogenic responses in mice with biliary fibrosis and accelerated fibrosis resolution[7]. Oral administration of Amlexanox (50mg/kg) twice daily for 30 days significantly reduced inflammatory infiltration and demyelination in the spinal cord tissue of the experimental autoimmune encephalomyelitis mouse model, and prevented weight loss in the mice[8].
References:
[1] Bailly C. The potential value of amlexanox in the treatment of cancer: Molecular targets and therapeutic perspectives[J]. Biochemical Pharmacology, 2022, 197: 114895.
[2] Zhang Y, Zhang J, Wang J, et al. Targeting GRK2 and GRK5 for treating chronic degenerative diseases: Advances and future perspectives[J]. European Journal of Medicinal Chemistry, 2022, 243: 114668.
[3] Liu Y, Lu J, Zhang Z, et al. Amlexanox, a selective inhibitor of IKBKE, generates anti-tumoral effects by disrupting the Hippo pathway in human glioblastoma cell lines[J]. Cell death & disease, 2017, 8(8): e3022-e3022.
[4] Phan Van T, Huyen Ton Nu Bao T, Leya M, et al. Amlexanox attenuates LPS-induced neuroinflammatory responses in microglial cells via inhibition of NF–κB and STAT3 signaling pathways[J]. Scientific Reports, 2024, 14(1): 2744.
[5] Cheng C, Ji Z, Sheng Y, et al. Aphthous ulcer drug inhibits prostate tumor metastasis by targeting IKKɛ/TBK1/NF-κB signaling[J]. Theranostics, 2018, 8(17): 4633.
[6] Reilly S M, Chiang S H, Decker S J, et al. An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice[J]. Nature medicine, 2013, 19(3): 313-321.
[7] Zhou Z, Qi J, Zhao J, et al. Dual TBK1/IKKɛ inhibitor amlexanox attenuates the severity of hepatotoxin‐induced liver fibrosis and biliary fibrosis in mice[J]. Journal of Cellular and Molecular Medicine, 2020, 24(2): 1383-1398.
[8] Quan M Y, Song X J, Liu H J, et al. Amlexanox attenuates experimental autoimmune encephalomyelitis by inhibiting dendritic cell maturation and reprogramming effector and regulatory T cell responses[J]. Journal of neuroinflammation, 2019, 16(1): 52.
Amlexanox (AA673)是一种具有口服活性的三环胺羧酸类化合物，可有效抑制TANK结合激酶1（TBK1）（IC50=0.8μM）和抑制因子κB激酶ε（IKK-ε）（IC50=5.8μM）[1]。Amlexanox选择性抑制G蛋白偶联受体激酶（GRK）5（IC50=8.86μM），在多种动物模型中作为抗炎和抗过敏免疫调节剂 [2]。
在体外，Amlexanox处理72小时可显著抑制U87和U251细胞增殖，IC50值分别为140μM和120μM[3]。6μM的Amlexanox处理24小时能显著降低脂多糖（LPS）(100ng/ml）诱导的小鼠BV2细胞和人HMC3小胶质细胞中促炎细胞因子和趋化因子表达[4]。5μM的Amlexanox处理PC3细胞7天可上调黏附分子（EpCAM、DSP、Claudin1、ZO1和E-钙黏蛋白）表达，并抑制间充质基因和整合素α5[5]。
在体内，雄性C57BL/6小鼠每日口服Amlexanox（25mg/kg；持续8周）可预防和逆转高脂饮食诱导的肥胖[6]。胆道纤维化小鼠每日口服50mg/kg剂量的Amlexanox（持续4周）能减轻肝纤维化反应并加速纤维化消退[7]。实验性自身免疫性脑脊髓炎小鼠模型每日两次口服50mg/kg剂量的Amlexanox（持续30天）可显著减少脊髓组织炎症浸润和脱髓鞘，并防止体重下降[8]。