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Hsp90 is a chaperone protein which promotes the folding and stability of a number of oncogenic proteins and therefore many oncogenic signals can be blocked simultaneously by inhibiting Hsp90. 17-(allylamino)-17-demethoxygeldanamycin (17AAG) is a benzoquinone ansamycin Hsp90 inhibitor and has promising anticancer activity in vitro, in animal models and in clinical trials. 17AAG has poor water-solubility which is a potential problem for clinical formulation. The hydroquinone derivative of 17AAG, 17AAGH2, is considerably more water soluble and previously we demonstrated that 17AAGH2 was a more potent Hsp90 inhibitor than its parent quinone. However, 17AAGH2 can be oxidized back to 17AAG under aerobic conditions so we tested the relative stability of 17AAGH2 and the effect of different metal ions and metal chelators on the oxidation of 17AAGH2. We found that copper could accelerate 17AAGH2 oxidation while copper chelators such as penicillamine could inhibit oxidation. Human serum albumin (HSA) has copper-binding ability and we also found that HSA could prevent 17AAGH2 oxidation. Sequestration of 17AAGH2 via non-covalent association with HSA could also explain the slower rate of oxidation of 17AAGH2 but we found that although 17AAG could associate with HSA, association was not observed with 17AAGH2. In summary, our data demonstrates that copper chelators can prevent 17AAGH2 oxidation and suggests that HSA prevents 17AAGH2 oxidation via a copper chelation rather than a sequestration mechanism. Agents that prevent oxidation may be useful in clinical formulations of 17AAGH2. (Supported by National Institute of Health grant R01 CA51210).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA