Abstract #4682: BIIB021, a fully synthetic oral small molecule inhibitor of Hsp90, shows anti-tumor activity in multiple xenograft models.

Abstract

BIIB021 is a novel synthetic oral inhibitor of heat shock protein 90 (Hsp90) that binds competitively in the Hsp90 ATP binding pocket. Hsp90 is a molecular chaperone that functions in the maturation and stabilization of cellular proteins. Hsp90, in complex with other co-chaperone proteins, catalyzes the conformational changes required for \#8220;client\#8221; protein function via its ATPase activity. 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. In cell-based assays with a variety of human cell lines, BIIB021 induced the degradation of HER-2 and other key client proteins including AKT, ERK, Raf-1, and EGFR. BIIB021 also caused upregulation of the expression of Hsp70 in a manner similar to other Hsp90 inhibitors. Oral administration of BIIB021 led to the degradation of HER-2, the induction of apoptosis and the inhibition of tumor growth in human tumor xenograft models that express high levels of HER-2 (BT474 and N87). BIIB021 also showed antitumor activity in the MCF-7 breast cancer xenograft model (that expressed lower levels of HER-2 and is estrogen receptor (ER) and progesterone receptor (PR) positive) and in the mutant EGRF NSCLC model H1650. Furthermore, the oral administration of BIIB021 in combination with molecularly targeted therapies enhanced the activity of monotherapy alone. BIIB021 is a promising new Hsp90 inhibitor that is fully synthetic and designed to be given orally, thereby supporting flexible therapeutic dosing schedules. BIIB021 is currently undergoing Phase 1 and Phase 2 clinical trials in hematological and solid tumors.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4682.