Cis-enone Resorcylic Acid Lactones (RALs) as Irreversible Protein Kinase Inhibitors

Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cisenone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders.