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 spe cific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. 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 r esorcylic acid lactone analogs. A preliminary structure-activity relationsh ip is presented. Several independent cell-based assays have been carried ou t to study the biological activities of these resorcylic acid lactone compo unds and a brief result summary from these studies is presented.