Discovery and Development of Ganetespib
Ganetespib is a potent second-generation inhibitor of heat-shock protein 90 (Hsp90), structurally consisting of a resorcinol moiety and a triazolone core. Ganetespib has shown robust anticancer activity against a broad variety of tumor cell lines where exposure resulted in the degradation of many well-known Hsp90 client proteins. In solid and hematological xenograft models of oncogene addiction, ganetespib has demonstrated potent antitumor efficacy both as a single agent and in combination with a number of widely used cancer therapeutics. Evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Pre-clinical results with ganetespib have shown a reduction of levels of hypoxia induced factor-1alpha (HIF-1α), suggesting that the compound can reduce or disrupt new blood vessel formation (angiogenesis) and the emergence of new lesions (metastases). Ganetespib possesses an excellent safety profile and shows no evidence of cardiac, liver or ocular toxicity. Ganetespib is being evaluated in a number of clinical trials including lung and breast cancers. In a Phase IIb global, randomized, multi-center study of ganetespib in combination with docetaxel in lung adenocarcinoma patients, a favorable safety profile as well as meaningful improvements in overall survival have been observed. Noteworthy clinical benefits have also been seen in additional clinical trials using ganetespib as monotherapy.