The 90 kDa heat shock proteins are proving to be extraordinary cancer chemotherapeutic targets as evidenced by the fact that 26 clinical trials are currently in progress. Unfortunately, all of these trials are based upon the N-terminal inhibitor, geldanamycin, which has serious formulation difficulties and produces toxicity unrelated to Hsp90 inhibition by virtue of its redox-active and electrophilic quinone ring. Only one total synthesis of this molecule has been reported, and the overall yield was 0.017% after 43 steps, suggesting that the preparation of analogues would be difficult. More recently, Neckers and coworkers determined that Hsp90 contains a C-terminal ATP binding site that bound coumarin antibiotics competitively versus ATP. Like N-terminal inhibitors, inhibitors of the C-terminal binding domain also cause the degradation of Hsp90-dependent client proteins involved in tumor cell growth and proliferation. A major drawback of the coumarin antibiotics is that they bind weakly to Hsp90 (IC50 approximately 700 micromolar); however, they remain the most potent C-terminal inhibitors described in the literature. We have recently identified a compound that is 700-7000 x's more active than the coumarin antibiotic in collaboration with Len Neckers and Jeff Holzbeierlein. This molecule has been evaluated in several tumor cell lines and has potent activity against a wide range of Hsp90 client proteins. In an effort to increase the potency of our lead molecule, we have proposed to incorporate functionalities that exist in the nucleotide specific substrates onto our lead compound to afford additional interactions with the Hsp90 C-terminal binding site. In addition, we propose to evaluate our lead compound in murine xenograft models of prostate cancer. Finally, it is proposed that by compromising the Hsp90 protein folding machinery with low doses of our lead compound, or any improved analogue, it will provide an acceptable concentration of other clinically used anti-tumor agents to induce apoptosis without detrimental side effects. As a consequence of these studies, we believe we can provide a basis upon which new inhibitors of the Hsp90 protein folding process can be developed without the deleterious side effects of the geldanamycin derivatives that are currently plagued in clinical trials. ? ? ?
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