Novel Monocarboxylate Transporter 1 and 4 Inhibitors: In Vitro and In Vivo Studies as Potential Anticancer Agents

Abstract

The primary goal of my research project is to develop novel drug candidates that target cancer cell glycolysis and oxidative phosphorylation via MCT1 and/or MCT4 inhibition for the treatment of cancers. We have discovered several candidate compounds based on CHC and coumarin templates with low nanomolar potency. The current research is innovative because the compounds presented in this thesis are among the very first to be used as dual monocarboxylate transporters 1 and 4 inhibitors (MCT1 and MCT4) for cancer treatment. These dual MCT1 and MCT4 inhibitors have low cell proliferation inhibition and are well tolerated in mice at high dosages. These inhibitors have been tested in in vivo tumor models and these studies indicate significant tumor growth inhibition in MCT1 expressing WiDr, 4T1-luc2 and GL261-luc2 and MCT4 expressing MDA-MB-231 xenograft/syngraft models. Our recently discovered highly potent dual MCT1 and MCT4 inhibitors are easy to synthesize, generally non-toxic, water soluble, and effective in arresting the tumor growth in vivo as single agents as well as in combination with clinical drugs. The impact of this project will be an enhanced, and improved anticancer agents and a longer and better quality of life for cancer patients with MCT1 and/or MCT4 expressing cancers. As MCT1 and/or MCT4 are expressed in a wide variety of cancers, these inhibitors can also be used as a broad-spectrum anticancer agents for the treatment of solid tumors.