Oct 31, 2021

Chem. (compared with oxidative phosphorylation), the rate of ATP generation is rapid. In addition, it is hypothesized that rapidly proliferating cancer cells have adapted this approach to regenerate NAD+ and to support the production of essential cellular building blocks such as amino acids, lipids, and nucleotides needed to support rapid cell growth.2 Indeed, many noncancer cells use a combination of oxidative phosphorylation and glycolysis to achieve the needed metabolic plasticity to serve their biological functions. Although the molecular basis of aberrant cancer metabolism and its role in cancer development and progression have yet to be fully elucidated,3 the Warburg effect and the enzymes in glycolysis have long been recognized Epoxomicin as potential targets for the selective killing of cancer cells. Epoxomicin Many glycolytic enzymes are overexpressed in cancer cells, including the lactate dehydrogenase (LDH) enzymes A (LDHA) and B (LDHB).4,5 LDH is a tetrameric protein composed of the products of (subunit M) and (subunit H) genes. The tetrameric combination of these gene products generates five LDH isoforms with different combinations of subunits depending on the cell type. The LDH5 (4 Epoxomicin M) isoform is the primary form expressed in cancer cells,6 although other isoforms Epoxomicin have also been reported. All LDH isoforms catalyze the last step in the glycolytic pathway converting pyruvate to lactate while regenerating NAD+ from reduced nicotinamide adenine dinucleotide (NADH). The lactate produced is then secreted from cells the monocarboxylate transporter proteins. Significant evidence exists to support the development of LDH inhibitors as a therapeutic option for cancer treatment. Genetic knockdown of has been shown to elicit cell death or delayed cell growth in cell lines from colorectal carcinoma (siRNA),7 Burkitt lymphoma (siRNA),8 hepatocellular carcinoma (siRNA),9 pancreatic cancer (shRNA),10 and mouse mammary tumor cells (shRNA).11 For example, mouse mammary tumor cells lacking LDHA implanted as xenografts demonstrated dramatically reduced tumor growth.11 In addition, in a genetically engineered mouse model of non-small-cell lung cancer, induced knockout of mouse LDHA led to the regression of established tumors without serious systemic toxicity.12 In contrast, LDHB knockdown has been reported not to significantly impact tumor cell survival.7 Although the therapeutic potential of LDHA inhibition appears to be substantial, the discovery and development of LDH inhibitors have proven to be challenging. For example, because of the micromolar concentrations of the LDH enzyme in cancer cells, an effective inhibitor will likely need to bind with exceptionally high affinity and also achieve high intracellular Rabbit polyclonal to ZNF345 concentrations to enable a therapeutic level of target engagement. To date, no inhibitors of LDH which meet these criteria have been reported. The first reported LDH inhibitors came from academic groups (inhibition of cellular lactate production and Epoxomicin cytotoxicity in cancer cells, but the relatively poor pharmacokinetics of these compounds limited their usefulness for testing of the therapeutic hypothesis was not demonstrated.18 Open in a separate window Figure 1. Representative previously described LDH inhibitors and comparison with new leads 43 = NCATS-SM1440 and 52 = NCATS-SM1441. aNamed as NCI-006 in refs 20 and 21. bNamed as NCI-737 in ref 20. We recently reported the identification of a pyrazole-based hit from quantitative high-throughput screening (qHTS) and used structure-based design to develop nanomolar inhibitors of LDH enzyme activity, exemplified by 1.19 Compound 1 inhibited LDH in highly glycolytic MiaPaCa-2 (human pancreatic cancer) and A673 (human Ewings.

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