Develpment of Novel Small Molecule Inhibotors for Cancer Research
Cancer is a disease of cell proliferation, and chemotherapeutic intervention strategies typically focus on selectively killing dividing cells in the body. Many of the drugs used as a last resort in the most aggressive cancers target the cellular architecture (or cytoskeleton) to stop cell division and kill these cells. However, these drugs also affect normal cells and have severe toxicity. Recent chemical biological approaches have focused on small organic molecules that inhibit a microtubule motor called Eg5 that functions in the formation of the mitotic spindle. Because Eg5 operates only during mitosis, it is thought that Eg5 inhibition will be less toxic than other drugs (such Taxol) that target microtubules. S-trityl-L-cysteine (STLC) has been identified as a highly specific, allosteric inhibitor of Eg5, and STLC-treatment of cells results in monopolar spindles, mitotic arrest, and cell death (De Bonis et al. Mol. Cancer Ther. 2004, 3, 1079). While STLC is a highly specific inhibitor of bipolar spindle formation in cell-based assays, the compound has poor pharmocokinetic properties that limit its therapeutic potential. The lines of experimentation outlined in this application will characterize the structure-activity relationship and develop improved analogs of STLC with increased efficacy for inhibiting cell division in vivo. We have completed initial experiments that establish the feasibility of our synthetic approach and validate the in vivo imaging assay used for measuring activity. A series of novel synthetic analogs will be assessed for their ability to inhibit Eg5 activity in vitro, and their ability to induce monopolar spindle formation in both human and nonmammalian cells. Promising compounds from this new class of cancer therapeutics will be screened against the tumor cell lines of the National Cancer Institute to determine their therapeutic potential. Expected project outcomes include both potential new cancer therapeutics and valuable new tools for basic research in cancer biology. These results will be published in high impact journals and offer opportunities for generating valuable intellectual property. This investigation will further establish interdisciplinary expertise in chemical biology and molecular targeting in the NMSU Bioscience Cluster, and lay a foundation for securing future external grant funding.