Ipi-504: A Novel Hsp90 Inhibitor With In Vitro And In Vivo Antitumor Activity

Abstract We have previously shown that inhibitors of the hsp90 molecular chaperone (including geldanamycin, 17-allylamino-17-demethoxy-geldanamycin (17-AAG) and other members of the ansamycin family) potently induce growth arrest and apoptosis of a large panel of drug-sensitive and -resistant MM cell lines, as well as tumor cells freshly isolated from patients with relapsed refractory MM; and sensitize these cells to other pro-apoptotic anti-tumor agents. While multiple phase I clinical trials have shown that biologically active doses of 17-AAG can be administered without significant hsp90-related toxicities, the insolubility of this compound in most conventional clinical solvents, as well as the practical limitations of DMSO-based formulations that were used in the original clinical trials have generated the need to develop more effective and practical approaches to administer 17-AAG to patients. Herein we describe the in vitro and in vivo pre-clinical profile of IPI-504, a novel analog of 17-AAG, which is soluble in aqueous formulations and can bypass key limitations of the DMSO-based formulations for administration of 17-AAG. Our in vitro studies show that IPI-504 has anti-tumor activity against a broad panel of primary MM tumor cells as well as MM cell lines (including cells resistant to cytotoxic chemotherapeutics, proteasome inhibitor bortezomib, thalidomide or its immunomodulatory thalidomide derivatives, and/or Apo2L/TRAIL). Based on hierarchical clustering analyses, logistic and linear regression models, we observed that the profiles of drug sensitivity of MM cells to IPI-504 were consistent with the profiles of sensitivity to 17-AAG. Similarly, IPI-504 triggered a constellation of molecular sequelae that were consistent with hsp90 inhibition by 17-AAG, including suppression of cell surface expression and down-stream signaling (via PI-3K/Akt and Ras/Raf/MAPK) of receptors for IGF-1 and IL-6; decreased intracellular levels of several key kinases, including Akt, Raf, IKK-α; suppressed expression of several intracellular anti-apoptotic proteins (e.g. FLIP, XIAP, cIAP2); leading to tumor cell sensitization to other pro-apoptotic agents (e.g. cytotoxic chemotherapy or PS-341). Importantly, in our mouse model of diffuse MM bone lesions in SCID/NOD mice, IPI-504 (50 mg/kg, i.v. twice weekly) was able to prolong the survival of mice vs. vehicle-treated mice (p<0.01, log-rank test), without significant treatment-related toxicities. These results indicate that hsp90 inhibitors have significant anti-MM activity in vivo, which, coupled with our ex vivo mechanistic and molecular profiling studies, have provided the framework for upcoming clinical trials of this novel class of agents in patients with MM.