VB124 is a safe, effective and orally active selective monocarboxylate transport protein 4(MCT4) inhibitor. VB124 blocks the input (IC50 = 8.6nM) and output (IC50 = 19nm) of lactic acid in MDA-MB-231 cells[1].
In vitro, mouse primary cardiomyocytes (ACM) subjected to hypoxia-reoxygenation were treated with VB124 to mitigate intracellular reactive oxygen species (ROS) levels and reduce cardiomyocyte apoptosis[2]. Treatment of HMCC97H and Hepa1-6 cells with VB124 (2,10μM) significantly inhibited lactic acid effusion caused by MCT4, reduced extracellular lactic acid levels, and further led to a decrease in glucose uptake and an increase in glutamine uptake[3].
In vivo, a single-dose oral administration of VB124 (30mg/kg) by gavage was used to create an acute cardiac ischemia-reperfusion model in mice. VB124 inhibited MCT4, resulting in a decrease in intracellular lactate and pyruvate levels, further exacerbating hypoxic injury caused by acute cardiac ischemia-reperfusion (I/R) in mice[2,4].
References:
[1]Cluntun AA, Badolia R, Lettlova S, Parnell KM, Shankar TS, Diakos NA, Olson KA, Taleb I, Tatum SM, Berg JA, Cunningham CN, Van Ry T, Bott AJ, Krokidi AT, Fogarty S, Skedros S, Swiatek WI, Yu X, Luo B, Merx S, Navankasattusas S, Cox JE, Ducker GS, Holland WL, McKellar SH, Rutter J, Drakos SG. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab. 2021 Mar 2;33(3):629-648.e10.
[2] Visker JR, Cluntun AA, Velasco-Silva JN, Eberhardt DR, Cedeño-Rosario L, Shankar TS, Hamouche R, Ling J, Kwak H, Hillas JY, Aist I, Tseliou E, Navankasattusas S, Chaudhuri D, Ducker GS, Drakos SG, Rutter J. Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart. JCI Insight. 2024 Jul 25;9(17):e180906.
[3]Fang Y, Liu W, Tang Z, Ji X, Zhou Y, Song S, Tian M, Tao C, Huang R, Zhu G, Jiang X, Gao J, Qu W, Wang H, Zhou P, Wu X, Jin L, Sun H, Ding Z, Peng Y, Zhao S, Zhou J, Fan J, Xu W, Shi Y. Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack. Hepatology. 2023 Jan 1;77(1):109-123.
[4]Tuineau MN, Herbert LM, Garcia SM, Resta TC, Jernigan NL. Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2024 Oct 1;327(4):L439-L451.
VB124是一种安全有效、具有口服活性的选择性单羧酸盐转运蛋白4(MCT4) 抑制剂，VB124阻断了MDA-MB-231细胞中的乳酸输入（IC50 = 8.6nM）和输出（IC50 = 19nM）[1]。
在体外，VB124处理通过缺氧再复氧的小鼠原代心肌细胞（ACM），降低胞内活性氧（ROS）水平，减少心肌细胞死亡[2]。VB124 (2、10μM)处理HMCC97H和Hepa1-6细胞，显著抑制MCT4导致的乳酸外排，降低细胞外乳酸水平，并进一步导致葡萄糖摄取减少和谷氨酰胺摄取增加[3]。
在体内，VB124（30mg/kg）单剂量口服灌胃后对小鼠造心脏急性缺血再灌注模型，VB124通过抑制MCT4，导致胞内乳酸和丙酮酸水平降低，进一步加重小鼠急性心脏缺血再灌注（I/R）导致的缺氧损伤[2,4]。