Human topoisomerase l (topo I) 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. However, the lack of high resolution structural information on drug binding is a major stumbling block in the design of new topo I poisons. We intend to develop protocols for the crystallization of human topo I in complex with one or another of the topo I poisons. These compounds bind to the transient covalent topo I-DNA complex, where they impede the relegation phase of catalysis and convert the enzyme into a DNA damaging agent. Our crystallization trials will be conducted with a series of innovative suicide substrates that permanently trap the covalent complex. All physiochemical parameters of the trials and their results will be captured in a relational database using proprietary Crystal Monitor(TM) software. Analysis of the captured information will accelerate the production of x-ray diffraction quality crystals of one or more ternary human topo 1-DNA-drug complexes. Success in this endeavor would provide an atomic resolution view of how topo I poisons interact with their target, and will enable Emerald BioStructures, Inc. to apply structure- based methods in the design of totally novel anticancer compounds that target human topo I.
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 who are diagnosed with cancer each year in the US, 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 the larger pharmaceutical companies that are developing topo I poisons for the treatment of human cancers. In addition, the information gained from a high resolution picture of the human topo I- poison complex would form the basis for a patent application wherein Emerald BioStructures, Inc. would seek to secure an ownership position with respect to certain novel classes of compounds that are predicted to be effective topo I poisons.
| Staker, Bart L; Feese, Michael D; Cushman, Mark et al. (2005) Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J Med Chem 48:2336-45 |
| 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 |
