1. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90.
- Author
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Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, Busch DJ, Neely L, Sensintaffar JL, Yang YC, McKenzie A, Friedman J, Scannevin R, Kamal A, Hong K, Kasibhatla SR, Boehm MF, and Burrows FJ
- Subjects
- Adenine administration & dosage, Adenine pharmacokinetics, Adenine pharmacology, Administration, Oral, Animals, Benzoquinones pharmacology, Blotting, Western, Cell Proliferation drug effects, Chromatography, High Pressure Liquid, HSP27 Heat-Shock Proteins metabolism, HSP70 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins metabolism, Humans, Lactams, Macrocyclic pharmacology, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-raf metabolism, Pyridines administration & dosage, Pyridines pharmacokinetics, Receptor, ErbB-2 metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Adenine analogs & derivatives, Antineoplastic Agents pharmacology, HSP90 Heat-Shock Proteins antagonists & inhibitors, Neoplasms, Experimental drug therapy, Pyridines pharmacology
- 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.
- Published
- 2009
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