Hsp90 is a widely-expressed molecular chaperone that functions in the maturation and stabilization of cellular proteins. Complexed together with other co-chaperone proteins, Hsp90 catalyzes the conformational changes of client proteins via its ATPase activity. The activity of Hsp90 maintains a variety of client proteins in their active conformation and plays an important role in the regulation of several key oncogenic signaling proteins. Mutant and over-expressed oncoproteins that drive malignant progression are particularly dependent on Hsp90 chaperone activity. In tumor cells inhibition of Hsp90 results in degradation of these proteins followed by cell death making Hsp90 a target of substantial interest for cancer therapy. The prototypic natural product drug, 17-AAG, has shown promise in early trials but is limited by poor pharmaceutic properties and hepatotoxicitiy. Here we describe BIIB021, a novel synthetic inhibitor of Hsp90. BIIB021 binds competitively with geldanamycin in the ATP binding pocket of Hsp90. In a flow cytometric assay designed to detect HER-2 protein levels treatment of MCF-7 cells with BIIB021 induced HER-2 degradation with an EC50 of 32nM. Western blot analysis after treatment of MCF7 cells with BIIB021 demonstrated the degradation of key client proteins including HER-2, Akt, and Raf-1 in a dose-dependent and time-dependent manner. As shown with other Hsp90 inhibitors the upregulation of expression of heat shock proteins Hsp70 and Hsp27 was also observed. In tumor cell growth assays treatment with BIIB021 led to growth inhibition and cell death at nanomolar concentrations. BIIB021 was tested two models that express high levels of the HER-2 oncoprotein, the BT474 breast and N87 gastric human tumor xenograft models. Oral administration of BIIB021 led to the degradation of the Hsp90 client protein HER2 and the potent inhibition of tumor growth in these models. BIIB021 also showed anti-tumor activity in the CWR22 prostate tumor model that expresses another Hsp90 client protein, the androgen receptor (AR). BIIB021 is a promising new Hsp90 inhibitor designed to be given orally and has potent preclinical anti-tumor activity. BIIB021 is currently undergoing Phase I clinical trials.

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA