Project 3:Isolation Chemistry of Filamentous Fungi and Biological Evaluation

PROJECT SUMMARY – PROJECT 3 There is a need for new anticancer drug leads, particularly for treating drug- resistant cancers. Fungi have been the source of many drug leads, with penicillin and the statins as two of the most prominent examples. It is hypothesized by Project 3 that fungi harbor anticancer drug leads, and we are addressing this via a team with expertise in mycology (Mycosynthetix, Inc./Pearce), natural products chemistry (UNCG/Oberlies), and chemical biology (Columbia/Stockwell). In the examination of thousands of fungal cultures from the Mycosythetix Inc.library, Project 3 has implemented biological and chemical protocols to prioritize our efforts. In doing so, we have identified hundreds of fungal metabolites with anticancer activity, approximately a third of which are new to the literature. Currently, we have prioritized three of these leads for further preclinical development, and our team is optimizing the biosynthesis of materials (targeting gram scale production) for pharmacology studies, PK/metabolism, and semi-synthetic optimization. One of these leads (verticillins) has shown a statistically significant response in an in vivo model of ovarian cancer. Another lead, eupenifeldin, showed a statistically significant response in an in vivo model of tumor resection in lung cancer. Both of these are undergoing further development, particularly lead optimization via semi-synthesis. A third lead is derived from fungal-fungal co-culture studies, which was an area of emphasis in the previous submission. An additional goal for generating new chemical diversity is the biosynthesis and/or semi-synthesis of non-natural natural products, via the incorporation of fluorine atoms into the privileged fungal-derived scaffolds. There are several areas documented in the proposal that demonstrate our team’s ability to leverage ideas and collaborations to further advance promising fungal metabolites.