The 90 kDa heat shock proteins are proving to be extraordinary cancer chemotherapeutic targets as evidenced by the fact that more than 20 clinical trials are currently in progress. Unfortunately, all of these trials are based upon N-terminal inhibitors, primarily geldanamycin- derived, which exhibit serious formulation, scheduling and dosing difficulties as these compounds induce Hsp's at the same concentration they induce client protein degradation. Previous studies by 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 required for tumor cell growth and proliferation. A major drawback of the coumarin antibiotics is that they bind weakly to Hsp90 (IC50 approximately 700 micromolar);however, recent studies by our group have led to compounds ~1000 fold more active than these natural products. Through SAR studies we have been able to identify functionalities important for Hsp90 inhibition and have learned how to modulate Hsp90 in ways not previously realized. Thus, we have developed compounds that induce Hsp's at low concentrations that refold denatured proteins as a new method to treat various neurodegenerative diseases. In contrast, we have constructed molecules that inhibit Hsp90 without inducing Hsp's, and therefore provide a mechanism by which to bypass difficulties observed with N-terminal inhibitors in the clinic. In this application we propose to further develop the anti-tumor agents based on a purine and CoMFA model developed in my laboratory that will aid in the construction of more efficacious and soluble inhibitors of the Hsp90 C-terminal binding site. In addition to our extraordinary preliminary in vivo studies, it is proposed to further investigate the most active compounds in additional in vivo models of cancer. As a consequence of these studies, we believe we can provide a new platform for which new drugs can be based or realized for the treatment of cancer via modulation of the Hsp90 protein folding machinery.
The goal of this proposal is to attack multiple cancer-enabling enzymes by targeting a protein (Hsp90) that is responsible for folding them, as all proteins must be folded to become active. Although clinical trials are in progress for compounds that target Hsp90, they exhibit detrimental properties that are proving difficult to overcome. We have identified molecules that do not exhibit these deleterious properties and have proven to be exceptional in preliminary animal models of cancer. We plan to continue and develop these drugs.
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