R 59-022

R 59-022 is a diacylglycerol kinase inhibitor (IC₅₀ = 2.8µM) ^[1]. R 59-022 can inhibit diacylglycerol kinase on the human erythrocyte membrane, resulting in a significant increase in diacylglycerol levels, a decrease in phosphatidic acid formation, and an increase in protein kinase C activity ^[1-2]. R 59-022 is often used to treat cancer ^[3-4].

In MCF10A cells, R 59-022 (1µM, 10µM, 100µM; 72h) reduces the survival rate of SCRIB-knockdown H-RAS ^G12V-expressing human mammary epithelial cells ^[4]. In VeroE6 cells, R 59-022 (2µM, 4µM; 4h) efficiently blocks EBOV GP-mediated entry into Vero cells ^[5]. In adrenal chromaffin cells, nicotine and potassium depolarization-induced calcium influx is blocked by R 59-022 (30µM; 10min) ^[6]. In Swiss 3T3 cells, R 59-022 (5µM; 4h) enhances bombesin-stimulated protein kinase C activity and DNA synthesis ^[7].

In glioblastoma xenograft therapy model, after daily intraperitoneal injection of the inhibitor R 59-022 (2mg/kg, 10mg/kg; ip; 13d), the average tumor volume of the treated mice was significantly smaller than that of the control mice ^[8]. In LCMV-infected Sh2d1a^−/− mice, R 59-022 (2mg/kg; ip; 4d) reduces the numbers of activated virus- specific CD8⁺ T cells ^[9].

References:
[1]. de Courcelles DD, Roevens P, Van Belle H. R 59 022, a diacylglycerol kinase inhibitor. Its effect on diacylglycerol and thrombin-induced C kinase activation in the intact platelet. Journal of Biological Chemistry. 1985 Dec 15;260(29):15762-70.
[2]. Nunn DL, Watson SP. A diacylglycerol kinase inhibitor, R59022, potentiates secretion by and aggregation of thrombin-stimulated human platelets. Biochemical Journal. 1987 May 1;243(3):809-13.
[3]. Liu K, Kunii N, Sakuma M, et al. A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response [S]. Journal of Lipid Research. 2016 Mar 1;57(3):368-379.
[4]. La Marca JE, Ely RW, Diepstraten ST, et al. A Drosophila chemical screen reveals synergistic effect of MEK and DGKα inhibition in Ras-driven cancer. Disease Models & Mechanisms. 2023 Mar 1; 16(3): dmm049769.
[5]. Stewart CM, Dorion SS, Ottenbrite MA, et al. A diacylglycerol kinase inhibitor, R-59-022, blocks filovirus internalization in host cells. Viruses. 2019 Mar 1; 11(3): 206.
[6]. Owen PJ, Jones JA, Boarder MR. Phosphatidic acid accumulation and catecholamine release in adrenal chromaffin cells: stimulation by high potassium and by nicotine, and effect of a diacylglycerol kinase inhibitor R 59 022. Journal of neurochemistry. 1991 Sep; 57(3): 769-774.
[7]. Morris C, Rice P, Rozengurt E. The diacylglycerol kinase inhibitor R 59022 potentiates bombesin stimulation of protein kinase C activity and DNA synthesis in Swiss 3T3 cells. Biochemical and biophysical research communications. 1988 Sep 15; 155(2): 561-568.
[8]. Dominguez CL, Floyd DH, Xiao A, et al. Diacylglycerol kinase α is a critical signaling node and novel therapeutic target in glioblastoma and other cancers. Cancer discovery. 2013 Jul 1; 3(7): 782-797.
[9]. Ruffo E, Malacarne V, Larsen SE, et al. Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1. Science translational medicine. 2016 Jan 13; 8(321): 321ra7.

R 59-022是一种二酰甘油激酶抑制剂（IC₅₀ = 2.8µM） ^[1]。R 59-022可抑制人红细胞膜上的二酰甘油激酶，导致二酰甘油水平显著升高、磷脂酸生成减少以及蛋白激酶C活性升高 ^[1-2]。R 59-022 常用于治疗癌症 ^[3-4]。

在MCF10A细胞中，R 59-022（1µM、10µM、100µM；72h）降低了SCRIB敲低、表达H-RAS ^G12V的人乳腺上皮细胞的存活率 ^[4]。在VeroE6细胞中，R 59-022（2µM、4µM；4h）能有效阻断EBOV GP介导的病毒进入Vero细胞 ^[5]。在肾上腺嗜铬细胞中，R 59-022（30µM；10min）能阻断尼古丁和钾去极化诱导的钙内流 ^[6]。在Swiss 3T3细胞中，R 59-022（5µM；4h）能增强铃蟾肽刺激的蛋白激酶C活性和DNA合成 ^[7]。

在胶质母细胞瘤异种移植治疗模型中，每日腹膜内注射抑制剂R 59-022（2mg/kg、10mg/kg；ip；13d）后，治疗组小鼠的平均肿瘤体积显著小于对照组小鼠 ^[8]。在感染LCMV的Sh2d1a^−/−小鼠中，R 59-022（2mg/kg；ip；4d）减少了活化的病毒特异性CD8⁺T细胞的数量 ^[9]。