tanespimycin

Tanespimycin (17-AAG; 17-allylamino-17-demethoxygeldanamycin) is a semisynthetic ansamycin antibiotic and a heat shock protein 90 (Hsp90) inhibitor investigated as an anticancer agent. Structurally related to geldanamycin, tanespimycin binds to the N‑terminal ATP-binding pocket of Hsp90, blocking its chaperone activity. Inhibition of Hsp90 disrupts folding and stability of numerous oncogenic client proteins (including kinases, steroid hormone receptors, and transcription factors), promoting their ubiquitination and proteasomal degradation and thereby impairing signaling pathways important for tumor growth and survival.

Preclinical studies demonstrated broad antitumor activity in vitro and in animal models, supporting clinical development. Tanespimycin entered multiple phase I and II clinical trials as a single agent and in combination regimens for cancers such as breast cancer (including HER2-positive disease), multiple myeloma, melanoma, and various solid tumors. Clinical development encountered challenges including hepatotoxicity and formulation and pharmacokinetic limitations; these issues, together with the emergence of newer Hsp90 inhibitors, limited further advancement. Tanespimycin has not received regulatory approval. Research on Hsp90 inhibition continues, with newer compounds and strategies aiming to improve potency, selectivity, safety, and drug-like properties.