Ruboxistaurin is an orally available inhibitor of protein kinase C (PKC), with IC50 values of 0.36µM, 0.0047µM, and 0.0059µM for PKCα, βI, and βII, respectively[1]. Ruboxistaurin can reduce the adhesion of macrophages to endothelial cells by lowering the expression of inflammatory cytokines and enhancing the antioxidant stress capacity of cells[2]. Ruboxistaurin has been widely used to reduce the degree of glomerular sclerosis and tubulointerstitial fibrosis in mice with kidney removal, and to improve renal function[3].
In vitro, Ruboxistaurin treatment for 24 hours significantly induced cell death in MOLM13 cells and MV4-11 cells, with IC50 values of 0.7µM and 1.5µM, respectively[4]. Treatment with 1µM Ruboxistaurin for 48 hours significantly inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) and phosphorylation of ERK1/2 and Akt[5]. Treatment with 1µM Ruboxistaurin for 6 days inhibited the overall size of the podosome actin belts in mouse bone marrow-derived macrophages (BMMs) induced by RANKL, resulting in a significant reduction in osteoclast formation[2].
In vivo, Ruboxistaurin treatment via oral administration at a dose of 10mg/kg/day for 6 weeks significantly reduced the mRNA expressions of TGF-β1, Smad2, and Smad3 in the kidneys of diabetic rats, and alleviated diabetic nephropathy[6]. Oral administration of Ruboxistaurin (0.5mg/kg) twice daily for 12 weeks effectively inhibited pre-retinal and optic nerve head neovascularization in the pig model of branch retinal vein occlusion[7].
References:
[1] Jirousek M R, Gillig J R, Gonzalez C M, et al. (S)-13-[(Dimethylamino) methyl]-10, 11, 14, 15-tetrahydro-4, 9: 16, 21-dimetheno-1 H, 13 H-dibenzo [e, k] pyrrolo [3, 4-h][1, 4, 13] oxadiazacyclohexadecene-1, 3 (2 H)-dione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase Cβ[J]. Journal of medicinal chemistry, 1996, 39(14): 2664-2671.
[2] Pang C, Wen L, Lu X, et al. Ruboxistaurin maintains the bone mass of subchondral bone for blunting osteoarthritis progression by inhibition of osteoclastogenesis and bone resorption activity[J]. Biomedicine & Pharmacotherapy, 2020, 131: 110650.
[3] Kelly D J, Edgley A J, Zhang Y, et al. Protein kinase C-β inhibition attenuates the progression of nephropathy in non-diabetic kidney disease[J]. Nephrology Dialysis Transplantation, 2009, 24(6): 1782-1790.
[4] Fedorov O, Marsden B, Pogacic V, et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases[J]. Proceedings of the National Academy of Sciences, 2007, 104(51): 20523-20528.
[5] Nakamura S, Chikaraishi Y, Tsuruma K, et al. Ruboxistaurin, a PKCβ inhibitor, inhibits retinal neovascularization via suppression of phosphorylation of ERK1/2 and Akt[J]. Experimental eye research, 2010, 90(1): 137-145.
[6] Al-Onazi A S, Al-Rasheed N M, Attia H A, et al. Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways[J]. Journal of Pharmacy and Pharmacology, 2016, 68(2): 219-232.
[7] Danis R P, Bingaman D P, Jirousek M, et al. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531[J]. Investigative ophthalmology & visual science, 1998, 39(1): 171-179.
Ruboxistaurin是一种口服有效的蛋白激酶C(PKC)抑制剂，对PKCα、PKCβI和PKCβII的IC50值分别为0.36µM、0.0047µM和0.0059µM [1]。Ruboxistaurin可通过降低炎症细胞因子的表达和增强细胞的抗氧化应激能力，减少巨噬细胞与内皮细胞的粘附[2]。Ruboxistaurin已被广泛用于减轻肾切除小鼠的肾小球硬化程度和肾小管间质纤维化，并改善肾功能[3]。
在体外，Ruboxistaurin处理24小时显著诱导了MOLM13细胞和MV4-11细胞的死亡，IC50值分别为0.7µM和1.5µM[4]。使用1µM的Ruboxistaurin处理人脐静脉内皮细胞(HUVECs)48小时，显著抑制了VEGF诱导的细胞增殖以及ERK1/2和Akt的磷酸化[5]。使用1µM的Ruboxistaurin处理小鼠骨髓来源的巨噬细胞(BMMs)6天，抑制了RANKL诱导的podosome actin环的整体大小，导致破骨细胞形成显著减少[2]。
在体内，每日口服10mg/kg剂量的Ruboxistaurin，连续6周，显著降低了糖尿病大鼠肾脏中TGF-β1、Smad2和Smad3的mRNA表达，并减轻了糖尿病肾病[6]。每日两次口服Ruboxistaurin（0.5mg/kg），连续12周，有效抑制了猪视网膜分支静脉阻塞模型中的视网膜前和视神经头新生血管形成[7]。