NB-598 is a potent, orally active, and competitive inhibitor of squalene epoxidase (SE)[1]. SE is an enzyme that catalyzes the conversion of squalene to squalene epoxide, a key step in cholesterol biosynthesis. By competitively binding to the active site of SE, NB-598 prevents the conversion of squalene, thereby reducing cholesterol production[2]. NB-598 is commonly used in studies investigating cholesterol regulatory mechanisms, the impact of cholesterol reduction on cellular processes and disease development, as well as in anti-diabetic research[3, 4].
In vitro, treatment of mouse pancreatic islets with NB-598 (10μM) for 48h dose-dependently inhibited both basal (1mM glucose) and high glucose (16.7mM glucose)-stimulated insulin secretion. This effect could be partially reversed by cholesterol supplementation. In MIN6 cells, mouse pancreatic islets, and human pancreatic islets treated with NB-598 (10μM) for 48h, total cholesterol levels were significantly reduced (by 36%, 40%, and 52%, respectively), and decreased cholesterol content was observed in subcellular structures such as the plasma membrane, endoplasmic reticulum, and insulin secretory granules[5]. Treatment of Huh7 and SMMC7721 cells with NB-598 (2μM) for 72h significantly inhibited cell viability and colony-forming ability[6].
In vivo, in C57BL/6 mice bearing subcutaneous H22 cell xenografts, oral administration of NB-598 (10mg/kg/day) for 8 treatments significantly suppressed tumor growth, reduced tumor weight, and decreased serum alpha-fetoprotein (AFP) levels[6]. In mice bearing H146 xenografts, oral administration of NB-598 (300mg/kg) led to sustained accumulation in tumor tissue and induced a significant increase in squalene, which persisted for up to 48h. In mice xenografted with LU139 cells, oral administration of NB-598 (300mg/kg/day; once daily) for 15 days significantly inhibited the increase in tumor volume[7].
References:
[1] HORIE M, TSUCHIYA Y, HAYASHI M, et al. NB-598: a potent competitive inhibitor of squalene epoxidase[J]. Journal of Biological Chemistry, 1990, 265(30): 18075-18078.
[2] NOWOSIELSKI M, HOFFMANN M, WYRWICZ L S, et al. Detailed mechanism of squalene epoxidase inhibition by terbinafine[J]. Journal of Chemical Information and Modeling, 2011, 51(2): 455-462.
[3] BROWN A J, CHUA N K, YAN N. The shape of human squalene epoxidase expands the arsenal against cancer[J]. Nature Communications, 2019, 10(1): 888.
[4] HIDAKA Y, HOTTA H, NAGATA Y, et al. Effect of a novel squalene epoxidase inhibitor, NB-598, on the regulation of cholesterol metabolism in Hep G2 cells[J]. Journal of Biological Chemistry, 1991, 266(20): 13171-13177.
[5] XIA F, XIE L, MIHIC A, et al. Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic β-cells[J]. Endocrinology, 2008, 149(10): 5136-5145.
[6] ZHANG Z, WU W, JIAO H, et al. Squalene epoxidase promotes hepatocellular carcinoma development by activating STRAP transcription and TGF-β/SMAD signalling[J]. British Journal of Pharmacology, 2023, 180(12): 1562-1581.
[7] MAHONEY C E, PIRMAN D, CHUBUKOV V, et al. A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition[J]. Nature Communications, 2019, 10(1): 96.
NB-598是一种有效的，具有口服活性和竞争性的角鲨烯环氧酶（SE）抑制剂[1]。SE是一种将角鲨烯转化为角鲨烯环氧化物的酶，是胆固醇生物合成的关键步骤。NB-598通过与SE活性位点竞争性结合，阻止角鲨烯的转化，从而降低胆固醇的生成[2]。NB-598通常用于胆固醇调节机制、降低胆固醇对细胞过程和疾病发展影响及抗糖尿病等的研究[3,4]。
在体外，NB-598（10μM）处理小鼠胰岛48h，剂量依赖性地抑制了基础（1mM葡萄糖）和高糖（16.7mM葡萄糖）刺激下的胰岛素分泌，该作用可通过胆固醇补充部分逆转。NB-598（10μM）处理MIN6细胞、小鼠及人胰岛48h，显著降低了总胆固醇水平（分别为36%、40%和52%），并在质膜、内质网和胰岛素分泌颗粒等亚细胞结构中均观察到胆固醇含量下降[5]。NB-598（2μM）处理Huh7和SMMC7721细胞72h，显著抑制了细胞的活力以及菌落形成的能力[6]。
在体内，NB-598（10mg/kg/day）通过口服灌胃治疗携带H22细胞皮下移植瘤的C57BL/6小鼠8次，显著抑制了肿瘤的生长，降低了肿瘤的重量和血清甲胎蛋白（AFP）的水平[6]。NB-598（300mg/kg）口服给药于携带H146异种移植瘤的小鼠，可在肿瘤组织中持续积累并诱导角鲨烯显著上升，持续至48h。NB-598（300mg/kg/day; once daily）口服给药异种移植LU139细胞的小鼠15天，显著抑制了肿瘤体积的增长[7]。