A novel small molecule inhibitor of heat shock protein 90 (Hsp90)

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Hsp90 is a molecular chaperone that maintains the conformation and activity of proteins involved in cellular processes such as cell growth, survival, differentiation and development. In addition a number of mutated client proteins required for tumor initiation, maintenance, and resistance are dependent on Hsp90 function for their stability.
 The first-in-class Hsp90 inhibitor 17AAG (17-allylamino-17-desmethoxygeldanamycin), a semi-synthetic derivative of the benzoquinone ansamycin geldanamycin, is currently in phase II clinical trials for cancer. Drugs based on this scaffold have dose-limiting hepatotoxicity which appears to be due to the presence of a reactive quinone moiety.
 A novel small molecule Hsp90 inhibitor series based on the natural compound radicicol, an Hsp90 inhibitor which does not have the intrinsic hepatotoxicity of benzoquinone ansamycins, has been designed, synthesized, and evaluated in various in vitro and in vivo models. These molecules have been modified so that they do not have the in vivo instability of radicicol. Several members of this series appear to bind Hsp90 in a different mode than geldanamycin or radicicol and exhibit higher affinity to Hsp90 than radicicol. NXD30001, the first active compound in the series, and its analogs efficiently inhibit cell proliferation and deplete multiple Hsp90 client proteins such as Her2, Akt, c-Raf, Cdk4, and Cyclin D1 in Her2-overexpressing breast and other cancer cell lines at low nanomolar concentrations. Pharmacokinetic studies demonstrate that NXD30001 can achieve potential therapeutic levels via intraperitoneal (i.p.) dosing and that the compound accumulates in tumors at above micromolar concentrations.
 Tumor pharmacodynamic analysis demonstrated depletion of multiple Hsp90 client proteins, including Her2, after a single dose; these client proteins remained undetectable for more than 2 days, consistent with the tumor PK data.
 NXD30001 demonstrated efficacy in breast cancer tumor xenograft models without evidence for liver and kidney toxicity. A number of analogs with activity similar to or better than NXD30001 have been synthesized and are being evaluated for oral bioavailability, tolerability, and efficacy in animal models. The potency, tolerability, pharmacokinetic and pharmacodynamic properties of NXD30001 and its derivatives indicate that it, or an analog, may be useful in the treatment of breast and other forms of cancer with an improved dosing and therapeutic window compared to 17AAG and possibly other Hsp90 inhibitors.