No abstract

Inhibition of heat shock protein 90 (Hsp90) results in the degradation of oncoproteins that drive malignant progression, inducing cell death, making Hsp90 a target of substantial interest for cancer therapy. BIIB021 is a novel, fully synthetic inhibitor of Hsp90 that binds competitively with geldanamycin in the ATP-binding pocket of Hsp90. In tumor cells, BIIB021 induced the degradation of Hsp90 client proteins including HER-2, AKT, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. BIIB021 treatment resulted in growth inhibition and cell death in cell lines from a variety of tumor types at nanomolar concentrations. Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models. Studies to investigate the antitumor effects of BIIB021 showed activity on both daily and intermittent dosing schedules, providing dose schedule flexibility for clinical studies. Assays measuring the HER-2 protein in tumor tissue and the HER-2 extracellular domain in plasma were used to show interdiction of the Hsp90 pathway and utility as potential biomarkers in clinical trials for BIIB021. Together, these data show that BIIB021 is a promising new oral inhibitor of Hsp90 with antitumor activity in preclinical models. [Mol Cancer Ther 2009;8(4):921-9] IntroductionHeat shock protein 90 (Hsp90) is a widely expressed molecular chaperone that functions in the maturation and stabilization of cellular proteins (1-3). Hsp90, in complex with other cochaperone proteins, catalyzes the conformational changes of client proteins via its ATPase activity (4). The activity of Hsp90 maintains a variety of client proteins in their active conformation (5). Hsp90 also plays an important role in the regulation of several key oncogenic signaling proteins (6-8) and steroid receptors (9). Mutated proteins are particularly dependent on Hsp90 for the maintenance of the active conformation (2, 3).Ansamycin drugs such as geldanamycin bind in the ATPbinding site in the NH 2 terminus of Hsp90 (6, 10). This binding inhibits the chaperone activity of Hsp90 and results in proteasomal degradation of the client proteins (5, 11-13). Because tumor cells rely on the activity of client proteins for cell proliferation and survival, drug-induced client protein degradation leads to cytostasis and/or selective cell killing of tumor cell in vitro and in vivo (14-16).The semisynthetic Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical trials for cancer (17)(18)(19). However, 17-AAG is expensive to prepare and difficult to formulate. The problematic nature of the formulations may well contribute to the dose-limiting toxicity observed with this compound. 17-AAG is also susceptible to metabolism by NQO1/DT-diaphorase enzymes (20) and to efflux by P-glycoprotein (21). The identification of a synthetic Hsp90 inhibitor would be of great therapeutic interest as it would circumvent t...

Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90α binding assay (IC(50) = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC(50) = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd × 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice.

No abstract

No abstract