R 59-022はジアシルグリセロールキナーゼ阻害剤(IC50 = 2.8µM)である[1]。R 59-022はヒト赤血球膜におけるジアシルグリセロールキナーゼを阻害でき、その結果、ジアシルグリセロールのレベルが著しく増え、ホスファチジン酸の形成が減り、タンパク質キナーゼC活性が増えた[1-2]。R 59-022は癌の治療によく使われる[3-4]。
MCF10A細胞で、R 59-022 (1µM, 10µM, 100µM；72時間)は、SCRIB-ノックダウンH-RAS G12V-発見のヒト乳腺上皮細胞の生存率を減らす[4]。VeroE6細胞で、R 59-022 (2µM, 4µM；4時間)は、Vero細胞へのEBOV GP-媒介の進入を効果的に遮断する[5]。副腎クロマフィン細胞で、ニコチンとカリウムの脱分極によるカルシウム流入はR 59-022 (30µM；10分間)に遮断される[6]。Swiss 3T3細胞で、R 59-022 (5µM；4時間)はボンベシン刺激のタンパク質キナーゼCの活性とDNA合成を増強する[7]。
神経膠芽腫異種移植治療モデルで、阻害剤R 59-022 (2mg/kg、10mg/kg；腹腔内注射；13日間)を毎日腹腔内注射した後、処理されたマウスの平均腫瘍体積は対照のマウスに比べて、ずっと小さかった[8]。LCMV-感染のSh2d1a−/−マウスで、R 59-022 (2mg/kg；腹腔内注射；4日間)は、活性化されたウイルス特異性のCD8+ T細胞の数を減らす[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.