Abstract
Glycolysis is the major energy producing pathway for fast growing, glycolytically dependent tumors, such as gliomas and ependymomas. Blocking glycolysis is, therefore, an important therapeutic strategy when used alone or as a combination therapy to enhance the effects of chemotherapy in energy‐starved tumors. In our previous studies, we examined D‐glucose‐based antimetabolites, including 2‐deoxy‐D‐glucose (2‐DG), and confirmed their ability to block glycolysis, discovered that they can induce autophagic cell death in vitro, and established their antitumor activity in vivo in an orthotopic glioma model.
However, during our evaluation of 2‐DG, we determined that these compounds do not possess sufficient drug‐like properties (reasonable biostability, pharmacokinetic characteristics, or distribution to the target) to warrant further investigations into their clinical effectiveness. In an attempt to improve the pharmacokinetic profile of 2‐DG, we have designed synthesized, and tested a series of ester‐type prodrugs that enhance biostability, biodistribution, and delivery of 2‐DG to its CNS target. We will present the synthesis and preliminary evaluation of these compounds, leading to the selection of WP1122 as our lead compound for further drug development. We will also present the subsequent evaluation of WP1122 in vivo in orthotopic brain tumor models and demonstrate its superior pharmacokinetic profile and enhanced CNS uptake.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C98.
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