ganetespib

Ganetespib, also known by its development code STA-9090, is a synthetic small-molecule inhibitor of heat shock protein 90 (Hsp90). It is described as a second-generation Hsp90 inhibitor designed to improve on some limitations of earlier agents.

Mechanism: Ganetespib binds selectively to the ATP-binding pocket of the N-terminal domain of Hsp90, inhibiting its chaperone activity. This results in the ubiquitin-proteasome–mediated degradation of multiple Hsp90 client proteins, including receptor tyrosine kinases and kinases such as HER2/ERBB2, EGFR, AKT, and RAF. The downstream effects include disruption of signaling pathways, reduced cancer cell proliferation, and induction of apoptosis.

Pharmacology and administration: Ganetespib is a synthetic small molecule administered intravenously in clinical studies. Developers have highlighted improvements in solubility and pharmacokinetic properties relative to first-generation Hsp90 inhibitors, enabling flexible dosing schedules in trials.

Clinical development: Ganetespib has been evaluated in preclinical studies and a range of phase I and II clinical trials, both as monotherapy and in combination with chemotherapy or targeted therapies, across various solid tumors and hematologic malignancies, including non-small cell lung cancer and breast cancer. Reported adverse events in trials commonly include fatigue, diarrhea, nausea, and cytopenias, with some occurrences of transient hepatic enzyme elevations. The program has demonstrated target engagement and modulation of signaling in tumors dependent on Hsp90 clients.

Status: As of the latest published information, ganetespib has not received regulatory approval for any indication. Several development efforts in different cancers were discontinued or redirected after early-phase results.