Abstract
Abstract Oncology drug discovery is constantly evolving by integrating new basic findings with established developmental practice. Two drug discovery platforms currently exist. One is an extension of basic research, rational drug design. Its alternative, one based on cytotoxicity, which qualifies leads by their ability to selectively kill cancer cells. Using this cytotoxicity based approach we recently discovered a novel synthetic small molecule we have called ON015640. This compound is highly effective at killing 15 different cancer cell lines with IC50 ranges from 20-90 nanomolar. The predominant phenotype associated with this compound is that of cellular rounding and detachment from substratum, a similar phenomenon to that observed during treatment of cultured cells with mitotic inhibitors like Taxol and Nocodazole. Using FACS, molecular mitotic indexing, and fluorescent microscopy we have subsequently demonstrated that ON015640 induces mitotic arrest and aberrant spindle formation. This mitotic arrest and spindle disruption can be attributed to this molecule's ability to depolymerize tubulin both in vitro and in vivo in a similar manner to Nocodazole. At effective concentrations this compound commences a program of mitotic catastrophe subsequently initiating effector caspases 3/7 and cleavage of Poly ADP Ribose Polymerase, primary steps in the activation of the intrinsic apoptotic pathway. Unlike classical tubulin depolymerizing agents, ON015640 is not a substrate for the ATP binding cassette family of efflux pumps and is capable of killing Multi Drug Resistant cell lines. This characteristic and the compound's nanomolar activity make it an attractive candidate for further development and characterization. To date, the exact site where ON015640 binds to tubulin remains unknown. Additionally, the pharmacokinetics and efficacy of this molecule have yet to be fully characterized. Thus, current and future efforts will be focused on establishing the dynamics by which ON015640 interacts with tubulin, while also developing this molecule into a clinically relevant drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4524. doi:10.1158/1538-7445.AM2011-4524
Published Version
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