Abstract
Abstract INTRODUCTION. Malignant glioma is one of the most lethal diseases in adulthood and remains refractory to the current therapies including chemoradiotherapies. The cancer stem cell theory dictates that brain tumor stem-like cells (BTSC) account for such intractability of malignant glioma. Recently, several molecularly-targeted therapies have demonstrated a varying degree of success in treatment of cancers including leukemia and breast cancer. In this study, we sought to determine the key kinases that regulate survival, self-renewal, and proliferation of BTSC, and to design novel small molecules by using the structure-based computantional modeling system. RESULTS. With the neurosphere cultures derived from our glioma patients, we identified 3 kinases that play vital roles in survival and/or proliferation of BTSC in vitro; Fibroblast Growth Factor Receptor 1, Aurora kinase B, and Maternal Embryonic Leucine-zipper Kinase. Structure-based computational modeling allowed us to perform in silico docking of various small molecule candidates to these kinases. As a result, four novel small molecules demonstrated highly specific targeting of the key structural elements of these kinases. We then synthesized these identified candidate compounds and confirmed their in vitro inhibition of the targeting kinase activities. Finally, we will also present our data about the treatment effect with these compounds on the in vitro BTSC growth and the in vivo tumor growth. CONCLUSION. Structure-based drug design will likely open up a new avenue to discover novel anti-cancer stem cell agents that can selectively target the key kinases in BTSC, leading to the growth arrest of malignant glioma. 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 3298. doi:10.1158/1538-7445.AM2011-3298
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