Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90

MEDI 210

James R. Porter, jporter@ipi.com, Jie Ge, Emmanuel Normant, Janid Ali, Marlene S. Dembski, Yun Gao, Asimina T. Georges, Louis Grenier, Roger Pak, Jon Patterson, Jens R. Sydor, Jim Wright, Julian Adams, and Jeffrey K. Tong. Infinity Pharmaceuticals, Inc, 780 Memorial Drive, Cambridge, MA 02139
IPI-504 is the hydroquinone hydrochloride salt of 17-allylamino-17-demethoxy-geldanamycin (17-AAG), an Hsp90 inhibitor that is currently in clinical trials for the treatment of cancer. IPI-504 demonstrates high aqueous solubility (>200 mg/mL). Interestingly, in vitro and in vivo IPI-504 interconverts with 17-AAG and exists in a pH and enzyme-mediated redox equilibrium. This occurs due to oxidation of the hydroquinone (IPI-504) to the quinone (17-AAG) at physiological pH and the reduction of 17-AAG by quinone reductases such as NQO1 to IPI-504. Here we report the design and synthesis of the stabilized hydroquinone IPI-504 and its inhibitory effect against Hsp90 and Grp94. Although IPI-504 was originally designed to be a soluble prodrug of 17-AAG, the hydroquinone is more potent than the quinone in the biochemical Hsp90 binding assay. Various hydroquinone analogs have been prepared to investigate the structure activity relationship of hydroquinone binding to Hsp90. Hydroquinone and quinone forms of 17-AAG metabolites show comparable binding affinities for Hsp90 and in cancer cell lines, hydroquinone analogs elicit specific responses consistent with Hsp90 inhibition. The desirable pharmacological properties as well as in vitro and in vivo activity of our lead compound, IPI-504, has led to the initiation of Phase I clinical trials in multiple myeloma.