Novel antibiotics are important tools both in research and medicine and are increasingly becoming better characterized as more is being discovered about their mechanisms. Geldanamycin is one such antibiotic. Produced by the Actinomycete Streptomyces hygroscopicus var. geldanus, it is structurally a benzoquinone ansamycin antibiotic. It has been shown to possess weak broad-spectrum antibiotic activity and potent anticancer activity.
Geldanamycin is useful in the study of the action of Heat Shock Proteins. It binds to Heat Shock Protein 90 (Hsp90) and alters its function. HSP90 client proteins are involved in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis. Hsp90 plays a major role in the folding and activation of several signaling proteins that promote the growth and survival of tumor cells. Geldanamycin, induces the degradation of these signaling proteins and, consequently, the death of malignant cells.
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Geldanamycin (in yellow) binds HSP90 (in blue, interacting side chains in red) in a well-defined deep pocket lined by residues conserved across different species expressing HSP90. Geldanamycin occupies the ATP-binding site on the protein. (2)
Antitumor effects of geldanamycin can be partly explained by the inhibition of oncoproteins such as v-Src, mutant p53 proteins, Raf-1, p185erbB2 proteins, and EGFR. Geldanamycin downregulates such target proteins as tyrosine kinases, steroid receptors, transcription factors and cell cycle regulatory kinases1,2. It induces the inactivation, destabilization and eventual degradation of HIF-1a. It also represents a potent inhibitor of p60src tyrosine kinase and of c-myc gene expression in murine lymphoblastoma cells.
Geldanamycin binds to Hsp90 and disrupts Raf-1- Hsp90 complex, leading to destabilization of Raf-14-7. It can inhibit conformational changes and stabilization by HSP90 which leads to target aggregation and ultimate degradation of these client proteins. Geldanamycin and its synthetic derivatives show higher affinity to HSP90 in tumor cells as compared to normal tissues and constitute a class of potential antitumor drugs. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate (namely, hepatotoxicity and minimal water solubility) that have led to the development of geldanamycin analogs such as 17-AAG (17-allylamino demethoxygeldanamycin) and 17-DMAG (17-dimethylaminoethylamino demethoxygeldanamycin hydrochloride).