ETC-1002 (ESP-55016)

ETC-1002 (ESP-55016) is a novel, once-daily oral lipid-lowering agent that inhibits adenosine triphosphate citrate lyase (ACL), an enzyme in the cholesterol synthesis pathway, and leads to upregulation of low-density lipoprotein cholesterol (LDL) receptors with half life between 15 and 24h^[1]. ETC-1002 also activates AMP-activated protein kinase (AMPK), a master kinase that regulates whole body energy metabolism and inhibits fatty acid and cholesterol synthesis pathways^[2].

In vitro, ETC-1002 (50 or 100μM) incubation on RAW264.7 murine macrophage cell for 1h before Pg-LPS (10μg/mL) stimulation ameliorated Pg-LPS-induced inflammation in RAW264.7 cells via the AMPK signaling pathway^[3]. ETC-1002 (100μM) treatment on hepatocellular carcinoma (HCC) cells overexpressing oncogene one cut homeobox 2 (ONECUT2) for 12h strongly increased AMPK phosphorylation and markedly inhibited cell migration and invasion, with the effects amplified by combined with the FGFR1 inhibitor PD173074^[4]. ETC-1002 (10μM) treatment on human intestinal epithelial NCM460 cells for 12h followed by LPS (1μg/ml) stimulation for 12h suppressed LPS-induced acetyl-CoA elevation and STAT3 acetylation^[5].

In vivo, ETC-1002 (30mg/kg/day) administrated into male Wistar Han rat refed a high-carbohydrate diet for two weeks via oral gavage reduced liver triglyceride, forkhead box protein O1 (FOXO1) and hepatocyte nuclear factor (HNF-4) protein levels, and reduced markers of oxidative metabolism^[6]. ETC-1002 (30mg/kg/day) administrated into thioglycollate-induced peritonitis mice models via oral gavage for 72h inhibited transmigration of both neutrophils and macrophages during the inception and propagation of inflammatory response by altering expression of matrix metalloproteinase^[7].

References:
[1] Saeed A, Ballantyne C M. Bempedoic Acid (ETC-1002): A Current Review. Cardiol Clin. 2018 May;36(2):257-264.
[2] Bilen O, Ballantyne C M. Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61.
[3] Li H Y, Zhang P P, Lin H B, Bao H, Yin J Y. ETC-1002 Attenuates Porphyromonas gingivalis Lipopolysaccharide-Induced Inflammation in RAW264.7 Cells via the AMPK/NF- κB Pathway and Exerts Ameliorative Effects in Experimental Periodontitis in Mice. Dis Markers. 2022 Mar 16:2022:8583674.
[4] Liu D F, Zhang T Y, Chen X P, et al. ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY. Cell Death Dis. 2021 Nov 27;12(12):1113.
[5] Li X Y, Xiang Z X, Wang X L, et al. Metformin attenuates colitis via blocking STAT3 acetylation by reducing acetyl-CoA production. J Adv Res. 2025 Mar 31:S2090-1232(25)00218-8.
[6] Pinkosky S L, Filippov S, Srivastava R A K, et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res. 2013 Jan;54(1):134-51.
[7] Filippov S, Pinkosky S L, Lister R J, et al. ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK. J Lipid Res. 2013 Aug;54(8):2095-2108.

ETC-1002 (ESP-55016) 是一种新型的每日一次口服降脂药物，可抑制腺苷三磷酸柠檬酸裂解酶（ACL），一种胆固醇合成途径中的酶，并导致低密度脂蛋白胆固醇（LDL）受体的上调，半衰期在15到24小时之间^[1]。ETC-1002还激活了腺苷酸活化蛋白激酶（AMPK），一种调节全身能量代谢的主控激酶，并抑制脂肪酸和胆固醇合成途径^[2]。

体外实验中，ETC-1002（50或100μM）孵育RAW264.7小鼠巨噬细胞1h后再用Pg-LPS （10μg/mL）刺激，ETC-1002通过AMPK信号通路减轻Pg-LPS诱导的RAW264.7细胞炎症^[3]。ETC-1002（100μM）作用于过表达促转移癌基因ONECUT2的肝细胞癌细胞12h，强烈增强AMPK磷酸化并显著抑制细胞迁移和侵袭，与FGFR1抑制剂PD173074联用时效应进一步扩大^[4]。ETC-1002（100μM）处理人肠上皮NCM460细胞12h后再用LPS（1μg/ml）刺激12h，抑制LPS诱导的乙酰辅酶A升高和STAT3乙酰化^[5]。

体内实验中，ETC-1002（30mg/kg/day）经灌胃给予高碳水化合物饮食饲养的雄性Wistar Han大鼠两周，降低肝脏甘油三酯、叉头框蛋白O1（FOXO1）和肝细胞核因子（HNF-4）蛋白水平及氧化代谢指标^[6]。ETC-1002（30mg/kg/day）经灌胃给予硫乙醇酸盐诱导的腹膜炎小鼠模型72h，通过改变基质金属蛋白酶（MMP）表达，抑制炎症起始与进展过程中中性粒细胞和巨噬细胞的迁移^[7]。