Abstract 3895: Rational design of small molecule inhibitors that bind to an allosteric pocket on human heat shock protein 70 (Hsp70)

Abstract

Abstract The 70 kDa heat shock protein (Hsp70) plays an important role in cancer and its pharmacological modulation with small molecules may represent a useful therapeutic approach. The discovery of such agents has been hampered by the lack of a full length crystal structure of human Hsp70. We constructed a homology model of the human Hsp70, which we investigated for potential druggable sites using SiteMap tool. An allosteric site in the nucleotide binding domain was identified and used to design potent Hsp70 modulators. Analysis of the Glide docking resulted in an understanding of important interactions between designed ligands, such as YK5, and the Hsp70 protein. When tested in breast cancer cells, YK5 led to depletion of onco-proteins, induced apoptosis and inhibited growth. YK5 is to our knowledge the first rationally designed small molecule inhibitor of Hsp70, and thus, represents a novel chemical tool to investigate its potential in cancer and other diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3895. doi:1538-7445.AM2012-3895