Resorcylic Acid Lactones: Naturally Occurring Potent and Selective Inhibitors of MEK

A resorcylic acid lactone, L-783, 277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783, 277 inhibits MEK with an IC50 value of 4nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783, 277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783, 290, the trans-isomer of L-783, 277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cellbased assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.