Research in the Potter lab has three major goals: Firstly, to develop novel approaches for the treatment of metastatic disease by selective prodrug activation at tumor sites in vivo; secondly, to generate small molecules that can modulate drug metabolism, with the ultimate goal of reducing non-specific toxicity; and finally to identify the mechanism of cytotoxicity of a class of compounds that alter RNA splicing. We employ a wide range of techniques from medicinal chemistry through molecular biology and in vitro studies, all the way to in vivo analyses.
For the past 14 years, the Potter lab has sought to understand the biology of carboxylesterases (CE), a class of enzyme responsible for the metabolism of xenobiotics, including numerous clinically used drugs. We have determined the crystal structure of the human liver hCE1, developed mutants that demonstrate improved activation of the anticancer prodrug CPT-11, and identified highly potent and selective inhibitors of these enzymes. In collaboration with Drs. Danks and Aboody, we have use neural progenitor cells (NPC) expressing CEs to target neuroblastoma tumor in vivo. The former co-localize with tumor cells in vivo and by engineering NPCs to express high levels of a secreted form of the CE we have deliver high levels of the enzyme to metastatic lesions. Following administration of CPT-11, we have demonstrated increased antitumor activity of the drug, resulting in elimination of metastatic disease from the animals. Current studies focus on developing these approaches for use in patients.
During the course of our biochemical analyses of the human CEs, we identified benzil as a highly potent inhibitor of this class of enzymes. Considerable medicinal chemistry and QSAR efforts demonstrated that the key pharmacophore consists of the ethane-1,2-dione moiety flanked by hydrophobic domains (see image below). Since the dose limiting toxicity for CPT-11 is delayed diarrhea, in part due to activation of the prodrug by CEs present within the intestinal epithelia, potentially these inhibitors may have therapeutic utility. Currently we are evaluating the ability of novel benzil analogues to modulate drug metabolism in vitro with candidate molecules being selected for in vivo analyses.
Tom Webb, in this department, has developed a series of compounds that specifically target the spliceosome, the cellular machinery responsible for the generation of bona fide mRNAs from nascent pre-RNA transcripts. These small molecules are potent cytotoxins, and appear to demonstrate selectivity for tumor cells. The mechanism by which these agents (Sudemycins) induce cell death is unclear, but we have established that they can induce alternative splicing of RNAs. Molecular analyses confirm that this occurs in numerous RNAs and we presume that this results in cellular stress leading to the initiation of the apoptotic cascade. Detailed molecular, bioinformatic and biochemical studies are currently underway to validate this hypothesis. Since the spliceosome represents a new target for drug design, we envisage that the Sudemycins may act as novel lead compounds with regard to cancer therapy.