Development of Drug Candidates Targeting Mitochondrial Bioenergetics for Cancer Treatment

Abstract

Cancer tumors have been shown to be metabolically heterogeneous in their means for acquiring bioenergetics, biosynthetic components for generating biomass, and controlling redox equilibrium. Differences in oxygen and nutrient availability, along with rapid proliferation, drives spatial metabolic phenotypes within a tumor. Having an adaptable metabolism allows for sustained growth in differing microenvironments. Metabolic adaptability of malignant tissues has posed a challenge for current therapies, as treatment of one metabolic pathway has been overcome by a compensatory upregulation of another pathway. Hence, targeting the ability of tumors to adapt their metabolism shows promise as a novel effective therapeutic strategy. In this regard, we have taken up two projects to inhibit metabolic heterogeneity in cancers. One project involves the design and synthesis of a novel small molecule inhibitor of mitochondrial pyruvate carrier (MPC), called D7. We have shown that D7 is specifically potent in highly energetic oxidative cancer cells, inhibits mitochondrial pyruvate import at nanomolar concentrations, and causes a monocarboxylate transporter 1 (MCT1) dependent intracellular accumulation of lactate. In addition, D7 has been shown to be well tolerated when administered in vivo, providing up to ~71% tumor mass reduction in a 67NR syngraft model and ~41% tumor mass reduction in a highly aggressive isogenic 4T1 syngraft model. The second project involves the repurposing of FDA approved metabolically targeting agents as anticancer agents. An extensive literature search in identifying FDA approved drugs or drug candidates with either glycolysis or oxidative phosphorylation (OxPhos) inhibition properties resulted in the selections of ~30 drugs for further evaluation. After preliminary evaluation in our lab, we further narrowed down our original list of ~30 drugs to 4 drug candidates: BAY-876 (glycolysis inhibitor), niclosamide (OxPhos inhibitor), and pyrvinium pamoate (OxPhos inhibitor) and IMD-0354 (OxPhos inhibitor). As single agents these candidate compounds were shown to induce compensatory metabolic pathways that were found to be suppressed when administered as combination therapies, highlighting the capacity for these candidates to be repurposed as anticancer agents targeting cancers metabolic adaptability. In addition, these candidate compounds were shown to be well tolerated in vivo in our lab, with single agent administration showing 61-68% tumor reduction in a 67NR syngraft model.