R-7050

R-7050 is a novel cell-permeable triazoloquinoxaline compound that selectively inhibited TNF-α induced cellular signaling^[2].

In RBL-2H3 cells R-7050 significantly reduced TNF proliferation when autophagy was also inhibited by Baf-A1^[7].CA to reduce cell viability in MDA-MB-231 breast cancer cells and tumorigenic HEK 293 cells but not in normal NIH3T3 fibroblast cells. Abundance of TNFA, TNF Receptor 1 (TNFR1) and cleaved caspase-8/-3 proapoptotic proteins to increase with CA treatment. Blocking of TNFA-TNFR1 signalling by small molecule inhibitor, R-7050, reduced the expression of cleaved caspase-8 and caspase-3 at the protein level^[3]. TRPA1 channel was positively expressed in the cell bodies and processes of HODs. The expression TRPA1 channel was significantly up-regulated by high concentration of TNF-α, which could be suppressed by R-7050^[5].

A single administration of R-7050 reduced neurovascular injury after ICH. In contrast to biologic approaches that directly bind and neutralize TNF-α activity, R-7050 selectively inhibits the association of TNFR with intracellular adaptor molecules, such as TRADD and RIP1, limiting receptor internalization and preventing subsequent cellular responses after TNF-α binding^[1]. Capsaicin, a selective TRPV1 agonist, increased ipsilateral afferent renal nerve activity in WT but not TRPV1-/- mice. WD intake increased leptin, IL-6, and TNF-α in adipose tissue, and TNF-α antagonist III, R-7050, decreased leptin in TRPV1-/--WD. The urinary albumin level was higher in TRPV1-/--WD than WT-WD^[4]. Treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters^[6].

References:
[1]. King MD, Alleyne CH Jr,et,al. TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett. 2013 May 10;542:92-6. doi: 10.1016/j.neulet.2013.02.051. Epub 2013 Mar 7. PMID: 23499961; PMCID: PMC3744337.
[2]. Gururaja TL, Yung S, et,al. A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1. Chem Biol. 2007 Oct;14(10):1105-18. doi: 10.1016/j.chembiol.2007.08.012. PMID: 17961823.
[3]. Pal A, Tapadar P, Pal R. Exploring the Molecular Mechanism of Cinnamic Acid-Mediated Cytotoxicity in Triple Negative MDA-MB-231 Breast Cancer Cells. Anticancer Agents Med Chem. 2021;21(9):1141-1150. doi: 10.2174/1871520620666200807222248. PMID: 32767960.
[4]. Zhong B, Ma S, et,al. Ablation of TRPV1 Elevates Nocturnal Blood Pressure in Western Diet-fed Mice. Curr Hypertens Rev. 2019;15(2):144-153. doi: 10.2174/1573402114666181031141840. PMID: 30381083; PMCID: PMC6635649.
[5]. Liu J, Que K, et,al. Tumor Necrosis Factor-α Regulates the TRPA1 Expression in Human Odontoblast-Like Cells. J Pain Res. 2020 Jul 6;13:1655-1664. doi: 10.2147/JPR.S255288. PMID: 32753941; PMCID: PMC7352379.
[6]. Wen Y, Lu X, et,al. KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis. J Am Soc Nephrol. 2019 Oct;30(10):1925-1938. doi: 10.1681/ASN.2019020111. Epub 2019 Jul 23. PMID: 31337692; PMCID: PMC6779357.
[7]. Ayo TE, Adhikari P, et,al. TNF Production in Activated RBL-2H3 Cells Requires Munc13-4. Inflammation. 2020 Apr;43(2):744-751. doi: 10.1007/s10753-019-01161-4. PMID: 31897916; PMCID: PMC7176528.

R-7050 是一种新型细胞渗透性三唑并喹喔啉化合物，可选择性抑制 TNF-α；诱导细胞信号传导^[2]。

在 RBL-2H3 细胞中，当自噬也被 Baf-A1 抑制时，R-7050 显着降低 TNF 增殖^[7].CA 降低 MDA-MB-231 乳腺癌细胞和致瘤性 HEK 293 细胞的细胞活力，但不影响正常的 NIH3T3 成纤维细胞。 TNFA、TNF 受体 1 (TNFR1) 和裂解的 caspase-8/-3 促凋亡蛋白的丰度随着 CA 处理而增加。小分子抑制剂 R-7050 阻断 TNFA-TNFR1 信号通路，在蛋白质水平上降低了裂解的 caspase-8 和 caspase-3 的表达^[3]。 TRPA1通道在HODs的细胞体和过程中呈阳性表达。高浓度 TNF-α 可显着上调 TRPA1 通道的表达，并可被 R-7050^[5] 抑制。

单次施用 R-7050 可减少 ICH 后的神经血管损伤。与直接结合和中和 TNF-α 的生物学方法相反；活性，R-7050 选择性抑制 TNFR 与细胞内衔接分子（如 TRADD 和 RIP1）的结合，限制受体内化并阻止 TNF-α 后的后续细胞反应；绑定^[1]。辣椒素是一种选择性 TRPV1 激动剂，可增加 WT 而非 TRPV1-/- 小鼠的同侧传入肾神经活动。 WD 摄入增加了瘦素、IL-6 和 TNF-α；在脂肪组织中，和 TNF-α；拮抗剂 III，R-7050，减少 TRPV1-/-WD 中的瘦素。 TRPV1-/--WD组的尿白蛋白水平高于WT-WD^[4]。在肾毒性血清肾炎期间使用 TNF 受体 1 抑制剂 R-7050 治疗可减少野生型小鼠和 KLF4 缺陷型巨噬细胞小鼠的损伤、纤维化和坏死性凋亡，并消除两组在这些参数上的差异^{[ 6]}.