The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt followed by their proteasomal degradation. Hsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage for cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and ureas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.

We report on the discovery of benzo- and pyridino- thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7'-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87 human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H- purin-6-ylamine).

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