Discovery of novel small molecules targeting cancer cell metabolism

2013-05-10Advanced age is a risk-factor common to most cancers. In coming years, a marked increase in the population aged 65 and over will compound the already dire need for improved anti-cancer drugs. Metabolic plasticity is an adaptive mechanism tumors rely upon for growth advantage. Without sufficient energy and biomass, cell replication cannot proceed. Therefore, the use of small molecules to interrupt cancer-specific metabolic processes presents a novel means to inhibit tumor growth. The clinical benefit of this approach has not yet been fully realized due to a lack of suitable agents targeting cancer cell metabolism. The research presented in this dissertation represents efforts directed at addressing this unmet need. TP compounds, a series of novel triphenylphosphonium salts were found to inhibit cell proliferation via accumulation in mitochondria, inhibition of oxygen consumption and increases in superoxide production. As single agents TP compounds slowed tumor growth in vivo. Mito-drugs prepared by conjugation of chlorambucil, doxorubicin or temozolomide to the triphenylphosphonium moiety redirected the these drugs to mitochondria. Redirecting drug uptake in this manner maintained or enhanced the antiproliferative activity of these agents in cell-based assays and could potentially improve therapeutic profiles in vivo. In another approach to metabolic targeting, the discovery of a novel class of sulfonamides targeting the glycolytic enzyme pyruvate kinase M2 is reported. The prototype molecule, AV220 and its close analogs inhibited cell proliferation and activated AMPK, the unfolded protein response, and increased autophagic flux. As a single agent, AV220 inhibited tumor growth in a mouse xenograft model of human colon cancer