Geldanamycin

Geldanamycin is a natural product antibiotic in the benzoquinone ansamycin family, produced by Streptomyces species such as Streptomyces hygroscopicus. It was identified for its antifungal and antitumor activities and is notable for its potent inhibition of heat shock protein 90 (Hsp90). The molecule features a macrocyclic ansa ring containing a benzoquinone moiety and a polyene side chain.

In biological systems, geldanamycin binds to the N-terminal ATP-binding pocket of Hsp90, inhibiting the chaperone’s ATPase activity. This prevents proper folding of multiple client oncoproteins (for example HER2, Raf, Akt), leading to their ubiquitin-proteasome–mediated degradation and suppression of signaling pathways that promote cell growth and survival. The effects are especially pronounced in cancer cells that rely on Hsp90-dependent signaling, but geldanamycin itself has limited clinical use due to toxicity and poor solubility.

Because of hepatotoxicity and pharmacokinetic limitations, geldanamycin analogs have been developed to improve tolerability and solubility. Notable derivatives include 17-AAG (tanespimycin) and 17-DMAG (alvespimycin), and retaspimycin (IPI-504), which have undergone clinical trials as Hsp90 inhibitors. Although results showed some anti-tumor activity, development has been hampered by adverse effects and limited efficacy in many indications, and geldanamycin and its derivatives are not approved as cancer therapies.

As a research tool, geldanamycin remains important for studying Hsp90 biology and the role of chaperone-assisted protein folding in cancer. Its discovery helped establish the strategy of targeting molecular chaperones in oncology.