Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone which modulates cellular homeostasis and environmental stress responses by interacting with more than 200 proteins, also known as Hsp90 client proteins, to facilitate their folding and maturation processes. Hsp90 comprises an N-terminal ATP-binding domain, a central domain that regulates the ATPase activity of the N-terminal domain, and a C-terminal domain that mediates constitutive Hsp90.
It was reported that Hsp90 can help tumor cells to maintain the malignant state with assistance of many oncoproteins, including Bcr-Abl, B-Raf, HIF-1α, mutated EGFR, HER2/neu, mutant p53, and many others, in a similar manner to normal cells. Accordingly, Hsp90 was suggested as a novel target for cancer therapy. Furthermore, the results of a study revealed that its inhibitors have the potential to target multiple cancer processes such as evading apoptosis, insensitivity to anti-growth signals, sustained angiogenesis, tissue invasion and metastasis, limitless replicative potential and self-sufficiency in growth signals.
A variety of Hsp90 inhibitors have been tested in preclinical and clinical trials. The first-generation of Hsp90 inhibitors are benzoquinone ansamycins, including geldanamycin and its derivatives tanespimycin (17-AAG) and alvespimycin (17-DMAG). However, the clinical progression of this group has been hampered because of several drawbacks including poor solubility, formulation problems, potential multidrug efflux, and hepatotoxicity. Also, as monotherapy, these inhibitors have only shown modest efficacies in the clinical setting, indicating that they may be useful only in combination therapies along with other cancer drugs. In an effort to overcome these limitations, several second-generation Hsp90 inhibitors featuring different chemotypes and potencies are currently under development. Among which, ganetespib and NVP-AUY992 are involved in most active clinical trials. The clinical trials of NVP-AUY922 are focused on combination therapy, whereas the focus for ganetespib lies on monotherapy as well as combination therapy of a variety of adaptations.
Ganetespib (3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole, STA-9090), a novel resorcinol-containing triazole compound unrelated to the ansamycin family of Hsp90 inhibitors, is one of the most promising Hsp90 inhibitor. It was reported that ganetespib displayed superior potency to the firstgeneration inhibitors and is currently in a phase III clinical trial led by Synta Pharmaceuticals. Herein, the current status and updates on the development of ganetespib will be described based on recent reports.
According to the patent for triazole-based Hsp90 inhibitors by Synta pharmaceuticals, it was suggested that ganetespib binds to the ATP-binding pocket at the N-terminus of Hsp90. Inhibition of Hsp90, in general, is thought to cause aberrant conformations of Hsp90 client proteins, which triggers ubiquitination-dependent degradation of client proteins via proteasomes. Ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to tanespimycin, and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regression. In particular, evaluation of the microregional activity of ganetespib in tumor xenografts showed that this compound was efficiently distributed throughout the tumor tissue, including the hypoxic regions >150 mm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity.
Altogether, inhibitors of Hsp90 are proven to achieve their promising anticancer activities through degradation of multiple oncoproteins within cancer cells. Gane tespib exhibited increased potency and better safety profiles in preclinical models over tanespimycin and has, so far, been safe in phase I clinical trials involving patients with solid tumors. Several phase II clinical trials are underway and a phase III clinical trial commenced at the time of publication. This preclinical activity profile showing select mechanistic and safety advantages over other first- or second-generation Hsp90 inhibitors indicates that ganetespib may have broad applications for a variety of human malignancies. The information from preclinical and clinical trials of ganetespib will be useful for development of cancer therapy with Hsp90 inhibitors and give positive impacts to subsequent applications of Hsp90 inhibitors.
Hyun Kyung Choi and Kyeong Lee. Arch Pharm Res Vol 35, No 11, 1855-1859, 2012