R 59-022는 다이아시릴글리세롤 키나제 억제제(IC50 = 2.8µM)이다. R 59-022는 인간 적혈구 막에서의 다이아시릴글리세롤 키나제를 억제해서 다이아시릴글리세롤 수준이 현저하게 증가하고 인지질산 형성이 감소하고 단백질 키나제 C 활성이 증가하게 된다[1-2]. R 59-022는 종종 암을 치료할 때 사용된다[3-4].
MCF10A 세포에서 R 59-022(1µM, 10µM, 100µM; 72시간)은 H-RAS G12V를 발현하는 SCRIB-knockdown 인 유방 상피세포의 생존율을 감소시킨다[4]. VeroE6 세포에서 R 59-022(2µM, 4µM; 4시간)은 EBOV GP를 매개로 Vero 세포로의 진입을 효율적으로 차단한다[5]. 부신 크로마핀 세포에서 니코틴과 칼륨 탈극화 유도 칼슘 유입은 R 59-022(30µM; 10분)에 의해 차단된다[6]. Swiss 3T3 세포에서 R 59-022(5µM; 4시간)은 개피 채소 자극 단백질 키나제 C 활성과 DNA 합성을 증강한다[7].
교모세포종 이종 이식 치료 모델에서 억제제 R 59-022(2mg/kg, 10mg/kg; ip; 13d)을 매일 복강내 주사한 후 처리된 쥐의 평균 종양 부피는 대조 그룹 쥐보다 현저하게 작았다[8]. LCMV 감염된 Sh2d1a−/− 쥐에서 R 59-022(2mg/kg; ip; 4d)은 활성화된 바이러스 특이적 CD8+ T 세포 수를 줄였다[9].
References:
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[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.