AS1517499 is a potent and brain-permeable STAT6 inhibitor with IC50 of 21 nM. AS1517499 often plays a role in the treatment of renal fibrosis and Keloids[1-2].
AS1517499 inhibited the proliferation of keloid fibroblasts (KFs) and normal skin tissue fibroblasts (NFs) with IC50 values of 1055-1958 nM and 3688-4130 nM, respectively, and AS1517499 significantly downregulated the expression of p-STAT6 in KF at 400 and 800 nM[2]. AS1517499 significantly downregulated the transcriptional levels of M2 macrophage-related genes (t IL−10 = 5.403, t TGF−β = 7.213, t CD206 = 48.940, t Arg1 = 11.253), and could also completely inhibit and block the STAT6/PPARγ pathway and the activation of macrophage M2 polarization[3].
AS1517499 (10 mg/kg ) can effectively reduce the levels of Th2-related cytokines in atopic dermatitis(AD) mice, alleviate airway eosinophil and lymphocyte infiltration, and regulate GATA3/Foxp3 levels and subepithelial collagen deposition[4]. AS1517499 (10 mg/kg) effectively inhibited the activation of STAT6 observed in mouse peritoneal macrophages and spleen after injection of zymosan. Furthermore, AS1517499 reduced the zymosan-mediated increase in IL-10, TGFβ, and HGF in peritoneal lavage fluid (PLF)[5].
References:
[1] Jiao B, An C, Tran M, et al. Pharmacological inhibition of STAT6 ameliorates myeloid fibroblast activation and alternative macrophage polarization in renal fibrosis[J]. Frontiers in immunology, 2021, 12: 735014.
[2] Chao H, Zheng L, Hsu P, He J, Wu R, Xu S, Zeng R, Zhou Y, Ma H, Liu H, Tang Q. IL-13RA2 downregulation in fibroblasts promotes keloid fibrosis via JAK/STAT6 activation. JCI Insight. 2023 Mar 22;8(6):e157091.
[3] Yan S W, Zhang R, Guo X, et al. Trichinella spiralis dipeptidyl peptidase 1 suppressed macrophage cytotoxicity by promoting M2 polarization via the STAT6/PPARγ pathway[J]. Veterinary Research, 2023, 54(1): 77.
[4] Li X, Han Z, Wang F, et al. The STAT6 inhibitor AS1517499 reduces the risk of asthma in mice with 2, 4-dinitrochlorobenzene-induced atopic dermatitis by blocking the STAT6 signaling pathway[J]. Allergy, Asthma & Clinical Immunology, 2022, 18(1): 12.
[5] Lee, Y.-J.; Kim, K.; Kim, M.; Ahn, Y.-H.; Kang, J.L. Inhibition of STAT6 Activation by AS1517499 Inhibits Expression and Activity of PPARγ in Macrophages to Resolve Acute Inflammation in Mice. Biomolecules 2022, 12, 447.
AS1517499 是一种有效的、可透过血脑屏障的 STAT6 抑制剂，IC50 为 21 nM。AS1517499常在肾纤维化及瘢痕的治疗中发挥作用[1-2]。
AS1517499 可抑制瘢痕疙瘩成纤维细胞（KFs）和正常皮肤组织成纤维细胞（NFs）的增殖，IC50 值分别为1055-1958 nM和3688-4130 nM，并且AS1517499在 400 和 800 nM 时能够大幅下调 KF 中 p-STAT6的表达[2]。AS1517499 明显下调M2巨噬细胞相关基因的转录水平（t IL−10 = 5.403，t TGF−β = 7.213，t CD206 = 48.940，t Arg1 = 11.253），还可以完全抑制并阻断STAT6/PPARγ通路以及巨噬细胞M2极化的激活[3]。
AS1517499（10 mg/kg ）可有效降低特应性皮炎（AD）小鼠Th2相关细胞因子水平，减轻气道嗜酸性粒细胞和淋巴细胞浸润，调节GATA3/Foxp3水平和上皮下胶原沉积[4]。AS1517499（10mg/kg ）有效抑制了注射酵母聚糖后在小鼠腹膜巨噬细胞和脾脏中观察到的 STAT6 的激活。此外，AS1517499 减少了腹腔灌洗液（PLF）中酵母聚糖介导的 IL-10 以及 TGFβ 和 HGF 的增加[5]。