Sotrastaurin (AEB071)
(Synonyms: 3-(1H-吲哚-3-基)-4-[2-(4-甲基哌嗪-1-基)喹唑啉-4-基]吡咯-2,5-二酮,AEB 071;AEB-071) 目录号 : GC15520
Sotrastaurin (AEB071)是一种强效、具有口服活性的泛蛋白激酶C（PKC）抑制剂，对PKCθ、PKCβ、PKCα、PKCη、PKCδ和PKCε的Ki值分别为0.22nM、0.64nM、0.95nM、1.8nM、2.1nM和3.2nM。
Cas No.:425637-18-9
Sample solution is provided at 25 µL, 10mM.
Sotrastaurin (AEB071) is a potent and orally-active pan-protein kinase C (PKC) inhibitor, with Ki values of 0.22nM, 0.64nM, 0.95nM, 1.8nM, 2.1nM and 3.2nM for PKCθ, PKCβ, PKCα, PKCη, PKCδ and PKCε, respectively[1]. PKC is a family of Ca²⁺- or diacylglycerol-dependent serine/threonine kinases that regulate cell proliferation, differentiation, apoptosis and immune responses by phosphorylating diverse downstream substrates[2]. Sotrastaurin is usually used in the research of autoimmune diseases and tumors[3].
In vitro, Sotrastaurin (1µM; 7 days) blocks PKC-driven proliferation and IL-17A/IFN-γ secretion while preserving Foxp3⁺CD25⁺ suppressive Treg phenotype in human CD4⁺ T cells[4]. Treatment of SUDHL-4 and OCI-LY8 DLBCL cells with Sotrastaurin (5-40µM; 48h) blocked cell proliferation, induced apoptosis, and triggered G1 arrest accompanied by down-regulation of MCT-1, cyclin D1, p-ERK and p-AKT and up-regulation of p53 and cleaved caspases-3/8/9[5].
In vivo, Sotrastaurin (10mg/kg; i.g.; every other day for 4–8 weeks) significantly reduced subchondral bone loss and articular cartilage degeneration, decreased TRAP⁺ osteoclast numbers, and improved OARSI scores in DMM-induced OA mice[6]. Sotrastaurin (30mg/kg; i.g.; twice daily for 3 days) reversed 30-h cold ischemia-induced hepatocellular necrosis and apoptosis, reduced serum ALT, and elevated elevating 14-day survival in syngeneic Sprague–Dawley rat orthotopic liver transplantation model[7].
References:
[1] Evenou JP, Wagner J, Zenke G, et al. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. J Pharmacol Exp Ther. 2009;330(3):792-801.
[2] Deka SJ, Trivedi V. Potentials of PKC in Cancer Progression and Anticancer Drug Development. Curr Drug Discov Technol. 2019;16(2):135-147.
[3] Sommerer C, Zeier M. AEB071--a promising immunosuppressive agent. Clin Transplant. 2009;23 Suppl 21:15-18.
[4] He X, Koenen HJPM, Smeets RL, et al. Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production. J Invest Dermatol. 2014;134(4):975-983.
[5] Chang G, Zheng J, Xiao W, et al. PKC inhibition of sotrastaurin has antitumor activity in diffuse large B-cell lymphoma via regulating the expression of MCT-1. Acta Biochim Biophys Sin (Shanghai). 2018;50(4):399-407.
[6] Pang C, Wen L, Qin H, Zhu B, Lu X, Luo S. Sotrastaurin, a PKC inhibitor, attenuates RANKL-induced bone resorption and attenuates osteochondral pathologies associated with the development of OA. J Cell Mol Med. 2020;24(15):8452-8465.
[7] Kamo N, Shen XD, Ke B, Busuttil RW, Kupiec-Weglinski JW. Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotopic liver transplantation. Am J Transplant. 2011;11(11):2499-2507.
Sotrastaurin (AEB071)是一种强效、具有口服活性的泛蛋白激酶C（PKC）抑制剂，对PKCθ、PKCβ、PKCα、PKCη、PKCδ和PKCε的Ki值分别为0.22nM、0.64nM、0.95nM、1.8nM、2.1nM和3.2nM[1]。PKC是一类钙离子或二酰甘油依赖的丝氨酸/苏氨酸激酶，通过磷酸化多种下游底物调控细胞增殖、分化、凋亡和免疫应答[2]。Sotrastaurin常用于自身免疫病和肿瘤研究[3]。
体外实验中，Sotrastaurin（1µM; 7天）可阻断PKC介导的增殖及IL-17A/IFN-γ分泌，同时维持人CD4⁺T细胞中Foxp3⁺CD25⁺的抑制性Treg表型[4]。用5-40µM Sotrastaurin处理SUDHL-4和OCI-LY8 DLBCL细胞48小时，可抑制细胞增殖、诱导凋亡并引发G1期阻滞，伴随MCT-1、cyclin D1、p-ERK和p-AKT的下调以及p53和裂解caspases-3/8/9的上调[5]。
体内实验中，Sotrastaurin（10mg/kg；灌胃；隔日一次，持续4-8周）显著减少DMM诱导的OA小鼠的软骨下骨丢失和关节软骨退化，降低TRAP⁺破骨细胞数量并改善OARSI评分[6]。Sotrastaurin（30mg/kg；灌胃；每日两次，持续3天）可逆转30小时冷缺血诱导的肝细胞坏死和凋亡，降低血清ALT，并将同源Sprague–Dawley大鼠原位肝移植模型的14天存活率提高[7]。
| Cell experiment [1]: | |
Cell lines | SUDHL-4 and OCI-LY8 DLBCL cells |
Preparation Method | The OCI-LY8 cell line was cultured in Iscove’s modified Dulbecco’s medium supplemented with 10% fetal bovine serum and 1% penicillin–streptomycin, and the SUDHL-4 cell line was cultured in RPMI 1640 containing 10% FBS and 1% penicillin–streptomycin. Cells were incubated in a humidified atmosphere at 37°C in 5% CO2. Sotrastaurin (40mM) was dissolved in dimethyl sulfoxide (DMSO) and stored at -20°C. SUDHL-4 and OCI-LY8 cells (0.1ml) were seeded into wells of 96- well plates at a density of 2×105cells/ml, treated with various concentrations of Sotrastaurin (5, 10, 15, 20, 25, 30, or 40μM) for 24, 48 or 72h in a 37°C incubator. At the end of the incubation, CCK-8 assay was used for cell proliferation detection. Cell apoptosis was measured using the Annexin-V/PI apoptosis detection kit. Cell cycle was assessed by flow cytometry. Protein was extracted for western blot analysis. |
Reaction Conditions | 5-40µM; 24-72h |
Applications | Treatment of SUDHL-4 and OCI-LY8 DLBCL cells with Sotrastaurin blocked cell proliferation, induced apoptosis, and triggered G1 arrest accompanied by down-regulation of MCT-1, cyclin D1, p-ERK and p-AKT and up-regulation of p53 and cleaved caspases-3/8/9. |
| Animal experiment [2]: | |
Animal models | C57BL/6 mice |
Preparation Method | A total of seventy-two 8-week-old C57BL/6 mice, 36 females and 36 males, were raised to the age of three months. Mice were then randomly assigned to one of six groups according to sex (n=6 mice each), including two groups of Sham-operated (intragastric administration of PBS only), two groups of medial meniscus (DMM) surgery and two groups of DMM+Sotrastaurin treatment (intragastric administration of 10mg/kg Sotrastaurin). For DMM surgery, mice were anaesthetized with chloral hydrate and then subjected to surgical transection of the medial meniscotibial ligament of the right knee. Sham mice received the same surgical procedure without the transection of the medial meniscotibial ligament. Two days post-surgery, mice were intragastrically administered with Sotrastaurin (treatment groups) or equivalent volume of PBS (Sham and DMM groups only) every other day for 4 or 8 weeks. No adverse reactions or animal fatalaties were recorded during the treatment period, and all mice exhibited normal behavioural activity. Mice were killed at the respective endpoints and the knee joints were excised, cleaned of soft tissues, fixed in 4% PFA, and then processed for micro-computed tomography (micro-CT) and histological assessments. |
Dosage form | 10mg/kg; i.g.; every other day for 4 or 8 weeks |
Applications | Sotrastaurin significantly reduced subchondral bone loss and articular cartilage degeneration, decreased TRAP⁺ osteoclast numbers, and improved OARSI scores in DMM-induced OA mice. |
References: | |
| Cas No. | 425637-18-9 | SDF | |
| 别名 | 3-(1H-吲哚-3-基)-4-[2-(4-甲基哌嗪-1-基)喹唑啉-4-基]吡咯-2,5-二酮,AEB 071;AEB-071 | ||
| 化学名 | 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione | ||
| Canonical SMILES | CN1CCN(CC1)C2=NC3=CC=CC=C3C(=N2)C4=C(C(=O)NC4=O)C5=CNC6=CC=CC=C65 | ||
| 分子式 | C25H22N6O2 | 分子量 | 438.48 |
| 溶解度 | ≥ 21.9mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2806 mL | 11.403 mL | 22.8061 mL |
| 5 mM | 456.1 μL | 2.2806 mL | 4.5612 mL |
| 10 mM | 228.1 μL | 1.1403 mL | 2.2806 mL |
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