Monorden (radicicol), a resorcylic 14-membered lactone, is a macrocyclic natural antibiotic initially isolated from the fungus Monosporium bonorden. Monorden was found to manifest antifungal and antitumor properties. It was shown to be an inhibitor of the v-Src and Ras-Raf-MAPK signaling pathways. Its ability to bind to heat shock protein Hsp90 made it the prototype of a second class of Hsp90 inhibitors, distinct from the chemically unrelated benzoquinone ansamycins. Radicicol inhibited Hsp90 activity by binding to the ATP-binding pocket, subsequently suppressing cell transformation induced by src, ras and mos. Radicicol binds more strongly to Hsp90 than to Grp94, the Hsp90 homolog that resides in the endoplasmic reticulum. In contrast to Hsp90, binding of radicicol to Grp94 requires both the N-terminal ATP/ADP-binding domain as well as the adjacent negatively charged region. Radicicol also specifically binds to yeast Hsp90, Escherichia coli HtpG, with greater homology to bacterial HtpG than to Hsp90 and to and a newly described tumor necrosis factor receptor-interacting protein, Trap-1. Radicicol displayed anti-cancer activity in vitro. It represses estrogen receptor transcriptional activity and inhibits angiogenesis. Radicicol disrupts the ER-Hsp90 heterodimeric complex, thereby generating ER-alpha that is susceptible to ubiquitin/proteasome-induced degradation. Because radicicol is rapidly metabolizes to inactive metabolites in vivo due to its electrophilic nature, no in vivo activity has been observed with this natural product including anti-tumor activity, thus the compound was not considered a viable candidate for clinical evaluation.