STA-9090 (Hsp90 INHIBITOR)

Program Overview

STA-9090 is a synthetic, small-molecule inhibitor of heat shock protein 90, or Hsp90, for the treatment of cancer. This program is currently enrolling in two Phase 1 clinical trials.

Hsp90 is an emerging therapeutic target of interest for the treatment of cancer. It is responsible for modulating cellular response to stress by maintaining the function of numerous signaling proteins – known as ‘client proteins’ – that are associated with cancer cell survival and proliferation. Many cancers result from specific mutations in, or aberrant expression of, these client proteins. Examples of cancer-associated client proteins of Hsp90 include c-KIT in gastrointestinal stromal tumors, epidermal growth factor receptor (EGFR) in lung cancer, and BCR-ABL in chronic myelogenous leukemia. In preclinical studies, inhibiting Hsp90 causes the degradation of these proteins and cancer cell death. Inhibiting Hsp90 has also proven effective in killing cancer cells that have developed resistance to targeted therapies such as kinase inhibitors.

STA-9090 was developed internally by Synta using our internal chemistry and drug optimization expertise to invent a novel chemical structure unrelated to the ansamycin family of Hsp90 inhibitors such as 17-AAG. In preclinical studies, STA-9090 has shown the ability to inhibit multiple kinases with comparable potency to, and a broader activity profile than specific kinase inhibitors such as imatinib (Gleevec®), erlotinib (Tarceva®), and sunitinib (Sutent®). In addition, STA-9090 has shown potency 10 to100 times greater than the ansamycin family of Hsp90 inhibitors, as well as activity against a wider range of kinases. In in vivo models, STA-9090 has shown strong activity in a wide range of cancer types, including cancers resistant to Gleevec, Tarceva, and Sutent. Based on our understanding of the mechanism, we believe STA-9090 may also provide additive or synergistic effects in combination with other anticancer treatments.

Phase 1 Trials: STA-9090 is currently enrolling patients in two dose-ranging Phase 1 clinical trials in solid tumors. The first trial is an open-label study in patients with solid tumors which is designed to identify the maximum tolerated dose of STA-9090 based on a twice-a-week intravenous dosing schedule. The second trial evaluates once-a-week intravenous dosing of STA-9090 in the same patient population. In addition to an evaluation of safety and tolerability, patients will be assessed for STA-9090 biological activity, based on biomarkers of Hsp90 inhibition, and response rate, based on the RECIST criteria.

References for Hsp90 Inhibition in Oncology

• TRENDS in Molecular Medicine, 2004, 10: 47 - 51: Altered states: selectively drugging the Hsp90 cancer chaperone.

• Nature, 2003, 425: 407 - 410: A high-affinity conformation of Hsp90 confers tumour selectively of Hsp90 inhibitors.