The signal transduction pathways that control tumor cell growth and survival provide an attractive, rational target for the development of new anticancer agents. A particularly effective approach to modulating these pathways could be provided by drugs which alter the function of heat shock proteins (Hsp) such as Hsp90 instead of anyone specific signaling molecule. These ubiquitously expressed molecular chaperones are not mutated in cancer. Instead, they appear to play an essential role in facilitating or enabling neoplastic transformation by enhancing the stability and activity of multiple oncogenic growth factor receptors, kinases and transcription factors. Over the past 5 years, several small molecule natural products have been identified as potential anticancer agents that interact with Hsp or their co-chaperones. One of these agents, 17 -N-allylamino-17 -demethoxygeldanamycin ( 17 MG ) has entered phase I clinical trials, but both 17 MG, and the other classes of Hsp-binding drugs identified so far suffer from serious limitations to their clinical utility including problems with solubility, metabolism, poor potency and/or limited specificity. To achieve the goal of exploiting Hsp as novel cancer chemotherapeutic targets, a need exists to find additional agents with which to modulate their complex cellular functions in vivo. Recently, a proprietary technology for characterizing and screening bioactive compounds has been developed by TELIK, Inc. that relies on the classification of a vast library of compounds according to their binding characteristics (""""""""fingerprints"""""""") against a panel of proteins. In contrast to traditional high throughput methods, this Target-Related Affinity Profiling (TRAP) approach allows the screening of a relatively small number of pure compounds, approximately 200-400, to identify active molecules against a specific molecular target or cellular pathway. We hypothesize that application of TRAP technology to data generated by reporter construct-based screens will allow us to identify new Hsp-binding compounds with the potential for clinical development. To test this hypothesis, we have assembled a multidisciplinary team with the expertise and infrastructure required to accomplish the following specific aims: 1) To identify potent compounds that alter Hsp function using a two stage series of moderate throughput, cell-based reporter assays and TRAP technology. 2) To identify the most promising compounds for further development by quantitating effects on proliferation, cell cycle progression, apoptosis and alterations in specific molecular targets such as erbB2, Akt, mutant p53 and steroid hormone receptors. 3) To evaluate the potential interaction of novel heat shock-active compounds with specific Hsp and co-chaperones using solid phase drug immobilization techniques. At a practical level these exploratory studies will provide new Hsp-active agents that can be used to further validate Hsp as targets for therapeutic intervention. The agents we identify can also serve as starting points for lead optimization in the development of useful anticancer agents with unique mechanisms of action. At a basic scientific level our application constitutes an innovative pharmacological approach to defining the mechanisms by which chaperones such as Hsp90 facilitate oncogenesis. Consequently, the insights gained in this project are likely to have significant implications for the more effective prevention and cure of cancer.
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