BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90

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...

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

“…3A and Supplementary Fig. S1), as previously reported (9,11,35,36), TAS-116 was more rapidly eliminated from retina (t 1/2 ¼ 3.4 hours) than the other HSP90 inhibitors (t 1/2 ¼ 7.1-19.1 hours), thereby demonstrating its lower retinal distribution profile (Fig. 3A and Supplementary Table S3).…”

“…It is possible that this excess liver toxicity is related to the quinone structure of ansamycin (16). The second generation of HSP90 inhibitors are based on a diverse variety of chemical scaffolds and exhibit less liver toxicity (11,13). However, these compounds cause other doselimiting toxicities, some of which are difficult to manage.…”

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

“…In these xenograft tumors, the suppression of specific sensitive client proteins lasted up to 72 h. HSP90 client proteins were suppressed for 24-48 h with NVP-AUY922, (30) for only 24 h following treatment with SNX-5422 (the pro-drug of SNX-2112), (20) and <24 h following treatment with BIIB021. (31) An overall review of the data for different HSP90 inhibitors in clinical development suggests a correlation between the potency of the inhibitors and their duration of action in tumors. The estimated K d of AT13387 for HSP90 was 0.7 nM, making it the most potent inhibitor at the N-terminal ATP site reported to date compared with other inhibitors (e.g.…”

“…(25)(26)(27) While there are many similarities in the pharmacology of these different agents, (28,29) one prominent variable is the duration of the pharmacodynamic effect reported. (20,30,31) We have used fragment-based drug discovery to identify the high-affinity, long-acting HSP90 inhibitor, AT13387, which is currently being evaluated in clinical trials. In the studies described here, we have used this inhibitor to demonstrate that maximizing the duration of effect in the target tissue enabled sustained client protein depletion and extended tumor growth inhibition with less frequent dosing of AT13387.…”

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

“…Antitumor efficacy ranges from minimal effects to tumor growth stasis but rarely tumor regression (9,14,15,(18)(19)(20). The variance in response between xenograft models may be attributable to differences in client protein dependence on Hsp90, tumor dependence on the client protein, kinetics of client protein degradation, and resynthesis, as well as, drug pharmacokinetic and pharmacologic properties.…”