SR 11302 is a retinoid-based, AP-1-selective transcription factor inhibitor that blocks AP-1 activity without activating retinoic acid response element (RARE)-mediated transcription[1]. AP-1 is a transcription factor dimer composed of proteins such as Jun/Fos, which regulates the expression of genes such as inflammation and proliferation by binding to the TRE sequence[2]. RARE serves as the cognate DNA element for the retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimer, propagating classic retinoid signaling[3]. By silencing AP-1 while remaining inert toward RAR/RXR, SR 11302 retains anti-inflammatory and anti-proliferative efficacy yet avoids the dermal toxicity, teratogenicity, and resistance associated with conventional retinoids[4]. SR 11302 is commonly used in studies of inflammation, oncology, and AP-1–mediated signaling pathways[5-7].
In vitro, pretreating AGS gastric epithelial cells with SR 11302 (2μM; 2h) and then infecting cells with H. pylori for 24 or 48h suppressed both cell proliferation and expression of oncogene proteins β-catenin and c-Myc[7]. In hypoxia-treated human pulmonary artery endothelial cells (HPAECs), SR 11302(1μM; 1h) abolished the hypoxia-evoked rise in aldosterone by blocking c-Fos/c-Jun–driven StAR transcription[8].
In vivo, oral administration of SR 11302 (o.5 or 1mg/kg/day) for 11 days in Vldlr−/− mice reduced the total vascular lesion number by 48% and decreased the lesion size by 40%, without detectable signs of toxicity in mice, including no change in body weight[5].
References:
[1] Fanjul A, Dawson MI, Hobbs PD, et al. A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature. 1994;372(6501):107-111.
[2] Karin M, Liu Zg, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997;9(2):240-246.
[3] Cunningham TJ, Duester G. Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell Biol. 2015;16(2):110-123.
[4] Huang C, Ma WY, Dawson MI, Rincon M, Flavell RA, Dong Z. Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid. Proc Natl Acad Sci U S A. 1997;94(11):5826-5830.
[5] Sun Y, Lin Z, Liu CH, et al. Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos. J Exp Med. 2017;214(6):1753-1767.
[6] Shiohara M, Dawson MI, Hobbs PD, et al. Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic proliferation and differentiation in vitro. Blood. 1999;93(6):2057-2066.
[7] Byun E, Park B, Lim JW, Kim H. Activation of NF-κB and AP-1 Mediates Hyperproliferation by Inducing β-Catenin and c-Myc in Helicobacter pylori-Infected Gastric Epithelial Cells. Yonsei Med J. 2016;57(3):647-651.
[8] Maron BA, Oldham WM, Chan SY, et al. Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis. Circulation. 2014;130(2):168-179.
SR 11302是一种类视黄醇类AP-1选择性转录因子抑制剂，能够阻断AP-1活性，而不激活视黄醇反应元件（RARE）转录[1]。AP-1是由Jun/Fos等蛋白组成的转录因子二聚体，通过结合TRE序列调控炎症和增殖相关基因的表达[2]。RARE是视黄醇受体（RAR）/视黄醇X受体（RXR）异二聚体的特异性DNA结合元件，介导经典的视黄醇信号传导[3]。通过抑制AP-1而不对RAR/RXR产生作用，SR 11302保留了抗炎和抗增殖的活性，同时避免了传统视黄醇类药物常见的皮肤毒性、致畸性和耐药性问题[4]。SR 11302常用于炎症、肿瘤和AP-1信号通路相关研究[5-7]。
体外研究中，用SR 11302（2 μM；2小时）预处理AGS胃上皮细胞，随后用幽门螺杆菌感染细胞24或48小时，可抑制细胞增殖以及β-catenin和c-Myc等癌基因蛋白的表达[7]。在缺氧处理的人肺动脉内皮细胞（HPAECs）中，SR 11302（1μM; 1小时) 通过阻断c-Fos/c-Jun驱动的StAR转录，消除了缺氧诱导的醛固酮水平升高[8]。
体内研究中，在Vldlr−/−小鼠中, SR 11302（0.5或1mg/kg/天）口服给药11天，可使总血管病变数量减少48%，病变大小缩小40%，且未检测到小鼠的毒性迹象，小鼠体重也无变化[5]。