BMS-303141 is a highly potent and cell-permeable ATP-citrate lyase (ACL) inhibitor with an IC50 value of 0.13μM[1]. ACL is a cytosolic enzyme responsible for the production of cytosolic acetyl-CoA, a precursor required for the de novo biosynthesis of cholesterol and fatty acids[2]. BMS-303141 can be used to block glycolytic activity and mitochondrial pyruvate carrier activity[3].
In vitro, treatment of ESCC cells with BMS-303141 (0-80μM) for 24-96h significantly inhibited cell survival and significantly reduced ACLY protein levels in a time- and dose-dependent manner[4]. Pretreatment of HUVEC cells with BMS-303141 (10μM) 4h before LPS stimulation reversed the LPS-induced upregulation of soluble vascular cell adhesion molecule 1 (VCAM-1), soluble E-selectin, and monocyte chemoattractant protein-1 (MCP-1) without affecting cell viability[5].
In vivo, oral administration of BMS-303141 (5mg/kg/day) for 8 days inhibited the growth of liver cancer cells in mice bearing HepG2 cell xenografts. Combination therapy of BMS-303141 and sorafenib significantly reduced tumor volume and weight and inhibited the expression of Ki-67 in tumor tissues[6]. Oral treatment of spontaneous type 2 diabetic mice with BMS-303141 (50mg/kg/day) for 30 days reduced the levels of serum lipids and renal lipogenic enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and HMG-CoA reductase (HMGCR), and alleviated ectopic lipid accumulation (ELA) and inflammation in the kidneys[7].
References:
[1] Li J J, Wang H, Tino J A, et al. 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors[J]. Bioorganic & medicinal chemistry letters, 2007, 17(11): 3208-3211.
[2] Pinkosky S L, Groot P H E, Lalwani N D, et al. Targeting ATP-citrate lyase in hyperlipidemia and metabolic disorders[J]. Trends in molecular medicine, 2017, 23(11): 1047-1063.
[3] Haggadone M D, Speth J, Hong H, et al. ATP Citrate Lyase Links Increases in Glycolytic Flux to Diminished Release of Vesicular Suppressor of Cytokine Signaling 3 by Alveolar Macrophages[M]//TP2. TP002 IMMUNOLOGY AND INFLAMMATION IN PULMONARY INFECTIONS. American Thoracic Society, 2021: A1268-A1268.
[4] Zhang X, Xu Y, Li S, et al. SIRT2‐mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma[J]. Journal of Cellular and Molecular Medicine, 2024, 28(6): e18129.
[5] Li R, Meng M, Chen Y, et al. ATP-citrate lyase controls endothelial gluco-lipogenic metabolism and vascular inflammation in sepsis-associated organ injury[J]. Cell Death & Disease, 2023, 14(7): 401.
[6] Zheng Y, Zhou Q, Zhao C, et al. ATP citrate lyase inhibitor triggers endoplasmic reticulum stress to induce hepatocellular carcinoma cell apoptosis via p‐eIF2α/ATF4/CHOP axis[J]. Journal of Cellular and Molecular Medicine, 2021, 25(3): 1468-1479.
[7] Zhan Z, Li A, Zhang W, et al. ATP-citrate lyase inhibitor improves ectopic lipid accumulation in the kidney in a db/db mouse model[J]. Frontiers in Endocrinology, 2022, 13: 914865.
BMS-303141是一种高效性的可渗透细胞的ATP-柠檬酸裂解酶（ACL）抑制剂，IC50值为0.13μM[1]。ACL是一种胞浆酶，负责产生胞浆乙酰辅酶A，乙酰辅酶A是胆固醇和脂肪酸从头生物合成所需的前体[2]。BMS-303141可用于阻断糖酵解活性和线粒体丙酮酸载体活性[3]。
在体外，BMS-303141（0-80μM）处理ESCC细胞24-96h，以时间和剂量依赖性方式显著抑制了细胞存活率，显著降低了ACLY蛋白水平[4]。在LPS刺激前4h用BMS-303141（10μM）预处理HUVEC细胞，逆转了LPS诱导的可溶性血管细胞粘附分子1（VCAM-1）和可溶性E-选择素以及单核细胞趋化蛋白-1（MCP-1）的上调，且不影响细胞活力[5]。
在体内，BMS-303141（5mg/kg/day）通过口服治疗HepG2细胞异种移植小鼠8天，抑制了小鼠的肝癌细胞生长，BMS-303141和索拉非尼联合治疗可显著减小肿瘤体积和重量，抑制了肿瘤组织中Ki-67的表达[6]。BMS-303141（50mg/kg/day）通过口服治疗自发性2型糖尿病小鼠30天，降低了小鼠的血清脂质和肾脏脂肪生成酶乙酰辅酶A羧化酶（ACC）、脂肪酸合酶（FAS）、HMG-CoA还原酶（HMGCR）的水平，减轻了肾脏中的异位脂质积累（ELA）和炎症[7]。