SB 204990, a lactone prodrug, potently inhibits ATP citrate-lyase [1]. SB 204990 reduces plasma cholesterol levels and triglyceride levels in animals by inhibiting ATP citrate lyase[2]. SB 204990 has been widely used in animal models to regulate the renal dysfunction induced by obesity and type 2 diabetes[3].
In vitro, SB 204990 treatment for 24 hours effectively inhibited the replication of SARS-CoV-2 WT, Delta, and Omicron variants in Caco2 cells, with IC50 values of 15.7µM, 13.1µM and 11.7µM, respectively[4]. SB 204990 treatment (40µM) for 24h significantly inhibited MDA-MB-231 cell viability in a glutamine-deficient medium[5]. Treatment with 100µM SB 204990 for 48 hours reversed galactose-induced β-Catenin activity and inhibited MC3T3 E1 cell differentiation into osteoblasts[6]. Treatment with 30µM SB 204990 for 48 hours inhibited TGF-β-stimulated proliferation and fibrin expression in cultured human cardiac fibroblasts (HCFs), reduced H3K9 and H3K27 acetylation [7].
In vivo, SB 204990 treatment via intraperitoneal injection at a dose of 135mg/kg/day for 14 days markedly reduced tumor growth in nude mice carrying xenografts of mouse pancreatic ductal cell lines bearing oncogenic K-rasG12D alleles[8]. Oral administration of SB 204990 at a dose of 250mg/kg/day for 15 weeks significantly improved metabolic status and physical health in high-fat diet (HFD)-fed C57BL/6 mice[9].
References:
[1] Pearce N J, Yates J W, Berkhout T A, et al. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids[J]. Biochemical Journal, 1998, 334(1): 113-119.
[2] van Vlijmenº B J M, Pearce N J, Bergö M, et al. Apolipoprotein E* 3-Leiden transgenic mice as a test model for hypolipidaemic drugs[J]. 1998.
[3] Li Y C, Chen Y, Deb D K. ATP‐Citrate Lyase is an Epigenetic Regulator to Promote Nephropathy in Obesity and Type 2 Diabetes[J]. The FASEB Journal, 2018, 32: 720.2-720.2.
[4] Yuen T T T, Chan J F W, Yan B, et al. Targeting ACLY efficiently inhibits SARS-CoV-2 replication[J]. International Journal of Biological Sciences, 2022, 18(12): 4714.
[5] Hatipoglu A, Menon D, Levy T, et al. Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells[J]. PLoS One, 2022, 17(10): e0276579.
[6] Busch M, White N, Shum L, et al. Active mitochondria support osteogenic differentiation by stimulating β-catenin acetylation[J]. Journal of Biological Chemistry, 2018, 293(41): 16019-16027.
[7] Kuwahara N, Nagao M, Shinohara M, et al. ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation[J]. Hypertension, 2025, 82(6): 1116-1128.
[8] Hatzivassiliou G, Zhao F, Bauer D E, et al. ATP citrate lyase inhibition can suppress tumor cell growth[J]. Cancer cell, 2005, 8(4): 311-321.
[9] Sola-García A, Cáliz-Molina M Á, Espadas I, et al. Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging[J]. Communications biology, 2023, 6(1): 250.
SB 204990是一种内酯前药，能够有效抑制ATP柠檬酸裂解酶活性[1]。SB 204990通过抑制ATP柠檬酸裂解酶，可降低动物体内的血浆胆固醇和甘油三酯水平[2]。SB 204990已广泛应用于调节肥胖及2型糖尿病引发的肾功能障碍的动物模型中[3]。
在体外，SB 204990处理24小时能有效抑制SARS-CoV-2野生株、Delta和Omicron变异株在Caco2细胞中的复制，IC50值分别为15.7µM、13.1µM和11.7µM[4]。在谷氨酰胺缺乏培养基中，使用40µM的SB 204990处理MDA-MB-231细胞24小时可显著抑制细胞活力[5]。用100µM的SB 204990处理MC3T3-E1细胞48小时，能够逆转半乳糖诱导的β-Catenin活性升高，并抑制MC3T3-E1细胞向成骨细胞分化[6]。以30µM的SB 204990处理培养的人心脏成纤维细胞(HCFs)48小时，可抑制TGF-β刺激的细胞增殖和纤维蛋白表达，同时降低H3K9和H3K27的乙酰化水平[7]。
在体内，通过每日腹腔注射135mg/kg/day剂量的SB 204990连续14天，能显著抑制携带致癌K-rasG12D等位基因的小鼠胰腺导管细胞移植瘤在裸鼠体内的生长[8]。每日口服250mg/kg/day剂量的SB 204990连续15周，可显著改善高脂饮食(HFD)喂养的C57BL/6小鼠的代谢状态和身体健康水平[9]。