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]。