Anti-tumor activity of a novel, water soluble Hsp90 inhibitor IPI-504 in multiple myeloma

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Heat Shock Protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. 17-AAG, a potent inhibitor of Hsp90 currently under clinical investigation suffers from poor aqueous solubility and must be administered to patients in either suboptimal DMSO formulations, or newer emulsion formulations. IPI-504 is a novel substance that is the chemical reduction product of 17-AAG resulting in the hydroquinone which is isolated as the hydrochloride salt. IPI-504 binds to Hsp90 more tightly than 17-AAG and exhibits excellent aqueous solubility enabling drug delivery as a simple i.v. infusion. Interestingly, in vitro and in vivo IPI-504 interconverts with 17-AAG and exists in a pH and enzyme-mediated dynamic redox equilibrium. As such, IPI-504 recapitulates all of the Hsp90 inhibitory properties and biological activity of 17-AAG without its formulation liabilities. Herein we describe findings in three areas of exploration with IPI-504: 1) In vitro and in vivo interconversion of IPI-504 with 17-AAG, 2) pharmacodynamics and selective tumor tissue uptake of IPI-504, and 3) scientific rationale and in vivo efficacy of IPI-504 in human xenograft and orthotopic models of multiple myeloma (MM). IPI-504 and 17-AAG are observed to interconvert in vitro in both liver microsomes as well as cell culture. Furthermore, IPI-504 or 17-AAG administered to mice, rats, or monkeys produces a dynamic equilibrium in vivo in which both species are present in plasma as well as tissue. This equilibrium is a balance of IPI-504 oxidation and 17-AAG enzymatic reduction. IPI-504 and 17-AAG are rapidly cleared from plasma within 4-6 hours, but are selectively retained in tumor tissue at pharmacologically active concentrations for up to 48 hours. Because of the 48 hour tumor tissue retention of IPI-504 and its active metabolites, tumor-bearing animals were administered drug either twice or thrice weekly. In the course of investigating the applicability of IPI-504 to the treatment of MM, we have discovered that IPI-504 is a potent suppressor of NF-κB activity, a transcription factor necessary for the growth and survival of MM in the bone marrow. Furthermore IPI-504 is active in vitro against MM cell lines and synergistically cytotoxic with the approved MM drug bortezomib. When RPMI8226 MM-bearing mice were treated with IPI-504 tumor reductions up to 71% were observed and directly correlated with overall reductions in serum levels of secreted λ chain antibody. Finally, significant increases in survival were observed in the MM1.s orthotopic myeloma model. We believe that IPI-504 in an aqueous solution has superior properties to existing 17-AAG formulations currently being tested in the clinic. The potential for IPI-504 as an anti-tumor agent will be explored in future clinical trials.