Quinoline 3-sulfonamides inhibit lactate dehydrogenase A (LDHA) and reduce lactate production in cancer cells. (A) Structures of the LDHA inhibitors and their potency on recombinant human LDH enzymes. (B) Potent LDHA inhibitors (Compounds 1 to 3) inhibit lactate production in Snu398 hepatocellular carcinoma cells whereas an analog that does not have LDHA inhibitory activity (Compound 4) does not affect cellular lactate. Lactate concentration in the conditioned medium was normalized to cell viability assessed by CellTiter Fluor™ assay (CTF), and the lactate/CTF ratio obtained in dimethyl sulfoxide -treated cells was set at 100%. Data are means ± standard error (SE) of at least five independent experiments with two replicates each. Half maximal effective concentrations (EC50) are means ± SE of at least five independent experiments. (C) Cancer cell lines exhibit different sensitivity to LDHA inhibition. Thirty-one cancer cell lines of different origins were analyzed in the lactate production assay described in (B). Data are means ± SD of at least two independent experiments with 2 replicates each. Heat maps of LDHA, LDHB, and combined transcript expression obtained from gene expression analysis are shown underneath the graph, with the darker color representing higher expression. Expression values in MAS5 units are listed in Additional file 3. MAS5 units are obtained by processing the data using Affymetrix MAS5 algorithm, with target value set at 100.