Abstract
Abstract Cancer cells exploit cellular stress response mechanisms, such as the unfolded protein response, to survive through cytotoxic treatments. A key mediator of the unfolded protein response, the 78kDa glucose regulated protein (GRP78) chaperone, has frequently been found to be overexpressed in breast cancer. In addition to providing a growth advantage to cancer cells, GRP78 induction leads to drug resistance. Suppressing GRP78 levels using siRNA has been shown to slow cancer cell progression and overcome drug resistance. Another approach to inactivating GRP78 is by inhibiting its ATPase activity. Currently, there are only few selective GRP78 inhibitors in development despite ample evidence of its critical role in cancer cell survival and drug resistance. Here, we report a novel class of small-molecule inhibitors of GRP78 ATPase activity. We designed a focused library of compounds based on a structure-based docking approach and screened for inhibition of GRP78 ATPase activity. Based of the initial hit, we further optimized several analogues with more potent activity and selectivity for GRP78 inhibition (IC50 <5μM). The lead compound, KR-240, induced CHOP significantly under conditions of ER stress and activated the pro-apoptotic arm of the unfolded protein response. KR-240 showed moderate cytotoxicity against a panel of breast cancer cell lines and increased sensitivity to chemotherapeutic agents, further supporting the role for GRP78 in cancer survival and drug resistance. Overall, our results indicate that our novel GRP78 inhibitor, KR-240 has the potential for further development as an anticancer agent. Citation Format: Kavya Ramkumar, Bikash Debnath, Amy S. Lee, Nouri Neamati. Design of GRP78 inhibitors as novel therapeutics for breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5678. doi:10.1158/1538-7445.AM2013-5678
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