Human topoisomerase I (topoI) is the sole intracellular target of camptothecin (CPT) and other """"""""topo I poisons,"""""""" some of which are among the most promising anticancer drugs ever identified. Emerald BioStructures, Inc. is actively engaged in a Phase I SBIR study that seeks to elucidate the X-ray crystal structure(s) of human topo I in complex with camptothecin (CPT) and derivatives thereof. We now seek """"""""Flexible"""""""" SBIR funds to broaden the scope of our structure-based approach toward designing new anticancer compounds. We propose to determine the X-ray crystal structures of human topo I in complex with novel indolocarbazoles and other non-CPT poisons that have demonstrated promising anticancer activities. The information gained from this endeavor will enable the intelligent Phase II design and synthesis of proprietary anticancer compounds that incorporate important structural features from a variety of topo I poisons. We also intend to pursue the X-ray crystal structures of CPT-resistant mutants of human topo I, as well as the complex formed between human topo I and SV40 Large T-antigen, a helicase that has been shown to interact with topo I (recapitulating a common theme in topoisomerase biology). These additional structure determinations will provide insights into the molecular mechanisms of drug resistance and the roles of other proteins in defining drug sensitivity, an essential component of any modern drug design effort.
The proposed research has immense commercial and humanitarian value since it will enable the rational design of new anticancer compounds that might one day be used to relieve the suffering of over 1.4 million people diagnosed with cancer each year in the U.S., and which spend an estimated $35 billion on available treatments. Success in Phase I is expected to provide multiple opportunities for collaborative research contracts with larger pharmaceutical companies that are developing topo I poisons for treatment of human cancers. In addition, the information gained from the X-ray structure determinations of the human topo I- poison complexes would form the basis for several patient applications on totally new classes of topo I poisons.
| Fox, Brian M; Xiao, Xiangshu; Antony, Smitha et al. (2003) Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. J Med Chem 46:3275-82 |
| Staker, Bart L; Hjerrild, Kathryn; Feese, Michael D et al. (2002) The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A 99:15387-92 |
