JR-AB2-011 is an improved mTORC2 inhibitor identified through structure-activity relationship (SAR) studies with an IC50 value of 0.36μM[1-2]. JR-AB2-011 was found to bind Rictor and inhibit its association with mTOR according to further mechanistic investigations[2].
In vitro, treating human chondrocytes with JR-AB2-011(50, 100, or 250µM) inhibited the activity of mTORC2 and prevented the inflammatory, catabolic, and apoptotic responses induced by IL-1β through the modulation of IκB-α/NF-κB activity[3]. Treating leukemia/lymphoma cells with 5µM JR-AB2-011 induced a rapid drop in the cell respiration rate, which was variably compensated by an increased glycolytic rate[4]. In RAW264.7 cells, mTORC2 was inhibited by 1μM JR-AB2-011, and JR-AB2-011 significantly blocked the effects of Dioscin and IL-4, leading to decreased expression of CD206, Arg-1, IL-10, and Ym1, as well as reduced uptake of free fatty acids[5].
In vivo, six-week-old male C57BL/6N mice treated with JR-AB2-011(20mg/kg; intraperitoneally) for 13 days showed a significantly decreased hepatic tumor burden after dissection[6]. Treatment with JR-AB2-011 (4mg/kg; i.p.) in BALB/c nude mice for 10 days significantly reduced tumor size, prolonged the survival of mice bearing X01-Luc (X01 GSC transduced with a luciferase-expressing vector) orthotopic xenograft tumors, and reduced the downstream gene expression involving mTOR2[7]. Rats were administered JR-AB2-011 (1mg/kg; i.p.), which reversed both the Zymosan-induced reduction in mean arterial pressure (MAP) and the increase in heart rate (HR), inhibited the enhanced expression of protein kinase B (Akt), IκB-α, IKKα, NF-κB p65, inducible nitric oxide synthase (iNOS), nitrotyrosine, cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β[8].
References:
[1] Zhang A, et al. CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats. Stroke Vasc Neurol. 2022 Jul 26;8(1):4–16.
[2] Benavides-Serrato A, Lee J, Holmes B, et al. Specific blockade of Rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma [retracted in: PLoS One. 2023 Sep 8;18(9):e0291490.]. PLoS One. 2017;12(4):e0176599.
[3] Temiz-Resitoglu M, Sabrie Z, Tiftik RN, et al. mTORC2 inhibition by JR-AB2-011 improves IL-1β-induced inflammation, catabolic response, and apoptosis in human chondrocytes through IκB-α/NF-κB p65. Cell Mol Biol (Noisy-le-grand). 2024;70(9):37-43.
[4] Kořánová T, Dvořáček L, Grebeňová D, Kuželová K. JR-AB2-011 induces fast metabolic changes independent of mTOR complex 2 inhibition in human leukemia cells. Pharmacol Rep. 2024;76(6):1390-1402.
[5] Wu MM, Wang QM, Huang BY, et al. Dioscin ameliorates murine ulcerative colitis by regulating macrophage polarization. Pharmacol Res. 2021;172:105796.
[6] Guenzle J, Akasaka H, Joechle K, et al. Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma. Int J Mol Sci. 2020;22(1):30.
[7] Zhou S, Lin W, Jin X, et al. CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells. Cell Rep Med. 2024;5(12):101844.
[8] Sabrie Z, Temiz-Resitoglu M, Kalkan T, et al. Protection by selective mTORC2 inhibition of Zymosan-induced hypotension and systemic inflammation mediated via IKKα/IκB-α/NF-κB activation. Prostaglandins Other Lipid Mediat. 2024;175:106918.
JR-AB2-011 是一种通过构效关系（SAR）研究发现的改进型 mTORC2 抑制剂，其半抑制浓度（IC50）为 0.36µM[1-2]。进一步的机制研究表明，JR-AB2-011 可以与 Rictor 结合并抑制其与 mTOR 的结合[2]。
在体外，用 JR-AB2-011（50、100 或 250µM）处理人软骨细胞，可以抑制 mTORC2 的活性，并通过调节 IκB-α/NF-κB 活性，防止由白细胞介素-1β（IL-1β）诱导的炎症、分解代谢和凋亡反应[3]。在白血病/淋巴瘤细胞中，使用 5µM 的 JR-AB2-011 处理会导致细胞呼吸速率迅速下降，而细胞通过增加糖酵解速率来不同程度地补偿这一变化[4]。在 RAW264.7 细胞中，1µM 的 JR-AB2-011 可以抑制 mTORC2 的活性，并且显著阻断了 Dioscin 和 IL-4 的作用，导致 CD206、精氨酸酶-1（Arg-1）、IL-10 和 Ym1 的表达降低，以及游离脂肪酸的摄取减少[5]。
在体内，6 周龄的雄性 C57BL/6N 小鼠通过腹腔注射接受 JR-AB2-011（20mg/kg）处理 13 天后，解剖发现肝脏肿瘤负荷显著减少[6]。在 BALB/c 裸鼠中，使用 JR-AB2-011（4mg/kg；腹腔注射）处理 10 天，可以显著缩小肿瘤体积，延长携带 X01-Luc（X01 胶质干细胞系转导荧光素酶表达载体）原位异种移植肿瘤的小鼠的生存期，并降低涉及 mTOR2 的下游基因表达[7]。在大鼠中，通过腹腔注射给予 JR-AB2-011（1mg/kg）可以逆转 Zymosan 诱导的平均动脉压（MAP）降低和心率（HR）增加，抑制蛋白激酶 B（Akt）、IκB-α、IKKα、NF-κB p65、诱导型一氧化氮合酶（iNOS）、硝酪氨酸、环氧化酶 2（COX-2）、肿瘤坏死因子（TNF）-α 和白细胞介素（IL）-1β 的增强表达[8]。