ATP citrate lyase inhibition can suppress tumor cell growth.

Many tumors display a high rate of glucose utilization, as evidenced by 18-F-2-deoxyglucose PET imaging. One potential advantage of catabolizing glucose through glycolysis at a rate that exceeds bioenergetic need is that the growing cell can redirect the excess glycolytic end product pyruvate toward lipid synthesis. Such de novo lipid synthesis is necessary for membrane production and lipid-based posttranslational modification of proteins. A key enzyme linking glucose metabolism to lipid synthesis is ATP citrate lyase (ACL), which catalyzes the conversion of citrate to cytosolic acetyl-CoA. ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor cells displaying aerobic glycolysis. The same treatments also reduce in vivo tumor growth and induce differentiation.

Identification of a pharmacophore for thrombopoietic activity of small, non-peptidyl molecules. 1. Discovery and optimization of salicylaldehyde thiosemicarbazone thrombopoietin mimics.

High-throughput screening has resulted in the discovery of thiosemicarbazone thrombopoietin mimics. A shared pharmacophore hypothesis between this series and a previously identified class, the pyrazol-4-ylidenehydrazines, led to the rapid optimization of both potency and efficacy of the thiosemicarbazones. The application of high-throughput chemistry and purification techniques allowed for the rapid elucidation of structure-activity relationships.

Identification of a pharmacophore for thrombopoietic activity of small, non-peptidyl molecules. 2. Rational design of naphtho[1,2-d]imidazole thrombopoietin mimics.

The invention of a new class of naphtho[1,2-d]imidazole thrombopoietin mimics based on a pharmacophore hypothesis for small-molecule thrombopoietic agonists is discussed. Parallel array synthesis and purification techniques allowed for the rapid exploration of structure-activity relationships within this class and for the improvement in TPO mimetic potencies and efficacies.

Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells.

BACKGROUND: Most normal cells in the presence of oxygen utilize glucose for mitochondrial oxidative phosphorylation. In contrast, many cancer cells rapidly convert glucose to lactate in the cytosol, a process termed aerobic glycolysis. This glycolytic phenotype is enabled by lactate dehydrogenase (LDH), which catalyzes the inter-conversion of pyruvate and lactate. The purpose of this study was to identify and characterize potent and selective inhibitors of LDHA. METHODS: High throughput screening and lead optimization were used to generate inhibitors of LDHA enzymatic activity. Effects of these inhibitors on metabolism were evaluated using cell-based lactate production, oxygen consumption, and 13C NMR spectroscopy assays. Changes in comprehensive metabolic profile, cell proliferation, and apoptosis were assessed upon compound treatment. RESULTS: 3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino) benzoic acid was identified as an NADH-competitive LDHA inhibitor. Lead optimization yielded molecules with LDHA inhibitory potencies as low as 2 nM and 10 to 80-fold selectivity over LDHB. Molecules in this family rapidly and profoundly inhibited lactate production rates in multiple cancer cell lines including hepatocellular and breast carcinomas. Consistent with selective inhibition of LDHA, the most sensitive breast cancer cell lines to lactate inhibition in hypoxic conditions were cells with low expression of LDHB. Our inhibitors increased rates of oxygen consumption in hepatocellular carcinoma cells at doses up to 3 microM, while higher concentrations directly inhibited mitochondrial function. Analysis of more than 500 metabolites upon LDHA inhibition in Snu398 cells revealed that intracellular concentrations of glycolysis and citric acid cycle intermediates were increased, consistent with enhanced Krebs cycle activity and blockage of cytosolic glycolysis. Treatment with these compounds also potentiated PKM2 activity and promoted apoptosis in Snu398 cells. CONCLUSIONS: Rapid chemical inhibition of LDHA by these quinoline 3-sulfonamids led to profound metabolic alterations and impaired cell survival in carcinoma cells making it a compelling strategy for treating solid tumors that rely on aerobic glycolysis for survival.