Resorcylic Acid Lactones as the Protein Kinase Inhibitors , Naturally Occuring Toxins

Abstract

Resorcylic acid lactones (RALs) are polyketide natural products with a large macrocyclic ring fused to a resorcylic acid residue. Some RALs contain an α,β-unsaturated ketone in the macrocycle. So far 46 kinases have been identified that could be potentially targeted by this family of compounds. RALs are of interest for their modulation of growth, and tentatively for the treatment of cancer and neurodegenerative diseases. RALs containing a cis-enone are susceptible to Michael addition reactions with the cysteine residue in the kinase nucleotide binding site, and thus serve as potent inhibitors of several protein kinases - they therefore represent a unique pharmacophore. Notably, this moiety has been shown to be effective also in vivo. This mini-review focuses on the structure and biological effects of the most important RALs, namely zearalenone, hypothemycin, pochonins, lasiodiplodins, aigialomycins, cochlicomycins, zaenols, and paecilomycins. Finally, the review also deals with radicicol, which is a nanomolar inhibitor of the chaperone Hsp90, whose suppression leads to a combinatorial block of cancer-causing pathways.