7ACC2

7ACC2, a carboxycoumarin derivative, is a potent inhibitor of monocarboxylate transporter 1 (MCT1), with an IC50 value of ~ 10 nM for lactate uptake in the human cervix carcinoma cell line SiHa. The family of MCT is composed of 14 members, among which only four isoforms (i.e. MCT1-4) have been documented to act as proton-linked transporters carrying short chain monocarboxylates such as lactate and pyruvate across cell membranes. In cancer cells, MCT1 and MCT4 are the most widely expressed, and MCT1 shows a better affinity for L-lactate than MCT4, enabling lactate entry into oxidative tumor cells. Thus, MCT1 blockade could serve as a potential therapeutic strategy to limit cancer progression. In addition, 7ACC2 is also a potent inhibitor of mitochondrial pyruvate transport, which interferes with pyruvate import into mitochondria and ultimately prevents extracellular lactate uptake as efficiently as a MCT1 inhibitor.

References:

1. Draoui N, Schicke O, Fernandes A, et al. Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells. Bioorganic & Medicinal Chemistry, 2013, 21(22): 7107-7117.

2. Corbet C, Bastien E, Draoui N, et al. Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects. Nature Communications, 2018, 9(1): 1208.