Background:Pyruvate dehydrogenase kinases (PDHKs), important metabolic and abnormally expressed enzymes in cancer cells, are promising targets for cancer therapy, especially for non-small-cell lung cancer (NSCLC). Methods:In this study, a new hit, dichloroacetophenone (DAP) analog 9, was postulated to bind to the PDHK1 allosteric pocket, guided by molecular modeling and kinase biochemical experiments. Based on this binding mode, novel DAP analogs were designed and synthesized to confirm the importance of Phe180, Tyr411, and the hydrophobic core at the bottom of the pocket. Results:This structure-activity relationship (SAR) study led to the discovery of a novel potent hybrid scaffold, dichloroacetophenone biphenylsulfone ether. Dichloroacetophenone biphenylsulfone ether 31 and 32 inhibited PDHK1 with IC50 values of 86 and 140 nM, respectively. Conclusion:Compound 32 with acceptable in vitro metabolic stability, predicted drug-likeness properties and ADME/T profiles, showed promising therapeutic efficacy in a lung cancer xenograft mouse model.

Pyruvate dehydrogenase kinase 1 (PDK1) is an important metabolic enzyme which is often overexpressed in many types of cancers, including non-small-cell lung cancers (NSCLC). Targeting PDK1 appears to be an attractive anticancer strategy. Based on a previously reported moderate potent anticancer PDK1 inhibitor, 64, we developed three dichloroacetophenone biphenylsulfone ethers, 30, 31 and 32, which showed strong PDK1 in-hibitions of 74%, 83% and 72% at 10 mu M, respectively. Then we investigated the anticancer effects of 31 in two NSCLC cell lines, namely, NCI-H1299 and NCI-H1975. It was found that 31 exhibited sub-micromolar cancer cell IC50s, suppressed colony formation, induced mitochondrial membrane potential depolarization, triggered apoptosis, altered cellular glucose metabolism, with concomitant reductions in extracellular lactate levels and enhanced the generation of reactive oxygen species in NSCLC cells. Moreover, 31 significantly suppressed the tumor growth in an NCI-H1975 mouse xenograft model, outperforming the anticancer effects of 64. Taken together our results suggested that inhibition of PDK1 via dichloroacetophenone biphenylsulfone ethers may provide a novel direction leading to an alternative treatment option in NSCLC therapy.

Cancer cells metabolize glucose via anaerobic glycolysis, with lactate formed in the cytosol as the end-product. To avoid intercellular acidification, excessive lactate and proton are excreted by monocarboxylate transporters (MCTs), which are often overexpressed in different malignant cancers. Targeting the MCT-mediated lactate/proton efflux makes MCTs a potentially interesting anticancer target. Although X-ray co-crystal structures of human MCTs with inhibitors are not yet available, homology models have been established, which helped to rationalize the binding modes and the design of new MCT inhibitors. In this review, we discuss the structures and functions of MCTs as well as recently reported small-molecule MCTs inhibitors. We assess the current development of MCT inhibitors and highlight possible directions for future development.