AR-C155858 is a potent inhibitor of monocarboxylate transporter 1 (MCT1) with a Ki value of 2.3nM, and also inhibits MCT2 with a Ki value of >10nM[1]. AR-C155858 has potential immunomodulatory and chemotherapeutic properties[2, 3]. MCT1 is expressed in most tissues and promotes lactate uptake for oxidation in cardiac and red skeletal muscle, as well as gluconeogenesis in the liver and kidney of some species[4]. AR-C155858 can inhibit the proliferation, migration, spheroid formation and in vivo tumor growth of TAMR-MCF-7 cells[5].
In vitro, treatment of 4T1 breast cancer cells with AR-C155858 (0-500nM) for 48h inhibited cell growth in a concentration-dependent manner with an IC50 value of 20.3nM, inhibiting cellular L-lactate uptake[6].
In vivo, AR-C155858 (5mg/kg) administered intravenously to rats co-administered with γ-hydroxybutyrate (GHB) and ethanol significantly reduced the respiratory depressant and sedative effects of the drug-drug interaction (DDI) of GHB and ethanol co-administration, and reduced the brain concentration and brain-to-plasma concentration ratio of GHB[7].
References:
[1] Guan X, Rodriguez-Cruz V, Morris M E. Cellular uptake of MCT1 inhibitors AR-C155858 and AZD3965 and their effects on MCT-mediated transport of L-lactate in murine 4T1 breast tumor cancer cells[J]. The AAPS journal, 2019, 21: 1-10.
[2] Wang Z H, Peng W B, Zhang P, et al. Lactate in the tumour microenvironment: From immune modulation to therapy[J]. EBioMedicine, 2021, 73.
[3] Wang H, Zhou F, Qin W, et al. Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies[J]. Theranostics, 2025, 15(6): 2159.
[4] Ovens M J, Davies A J, Wilson M C, et al. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10[J]. Biochemical Journal, 2010, 425(3): 523-530.
[5] Choi M C, Kim S K, Choi Y J, et al. Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells[J]. Archives of Pharmacal Research, 2023, 46(11): 907-923.
[6] Guan X, Bryniarski M A, Morris M E. In vitro and in vivo efficacy of the monocarboxylate transporter 1 inhibitor AR-C155858 in the murine 4T1 breast cancer tumor model[J]. The AAPS journal, 2018, 21(1): 3.
[7] Rodriguez-Cruz V, Morris M E. γ-Hydroxybutyric Acid–Ethanol Drug-Drug Interaction: Reversal of Toxicity with Monocarboxylate Transporter 1 Inhibitors[J]. The Journal of Pharmacology and Experimental Therapeutics, 2021, 378(1): 42-50.
AR-C155858是一种强效的单羧酸转运蛋白1（MCT1）抑制剂，Ki值为2.3nM，也能抑制MCT2，Ki值>10nM[1]。AR-C155858具有潜在的免疫调节和化疗特性[2, 3]。MCT1在大多数组织中表达，并促进乳酸摄取，以便在心脏和红色骨骼肌中氧化，以及在某些物种的肝脏和肾脏中发生糖异生[4]。AR-C155858能够抑制TAMR-MCF-7细胞的增殖、迁移、球状体形成和体内肿瘤生长[5]。
在体外，AR-C155858（0-500nM）处理4T1乳腺癌细胞48h，以浓度依赖性方式抑制了细胞生长，IC50值为20.3nM，抑制了细胞L-乳酸摄取[6]。
在体内，AR-C155858（5mg/kg）通过静脉注射治疗γ-羟基丁酸（GHB）和乙醇共同给药处理的大鼠，显著降低了GHB和乙醇共同给药对该药物相互作用（DDI）的呼吸抑制和镇静的影响，并降低了GHB的脑浓度和脑与血浆浓度比[7]。