title: Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK.
abstract: 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 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 resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based 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.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zhao
authors.forename: S H
authors.initials: SH
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Mojena
authors.forename: R G
authors.initials: RG
authors.lastname: Jenkins
authors.forename: D R
authors.initials: DR
authors.lastname: Patrick
authors.forename: H E
authors.initials: HE
authors.lastname: Huber
authors.forename: M A
authors.initials: MA
authors.lastname: Goetz
authors.forename: O D
authors.initials: OD
authors.lastname: Hensens
authors.forename: D L
authors.initials: DL
authors.lastname: Zink
authors.forename: D
authors.initials: D
authors.lastname: Vilella
authors.forename: A W
authors.initials: AW
authors.lastname: Dombrowski
authors.forename: R B
authors.initials: RB
authors.lastname: Lingham
authors.forename: L
authors.initials: L
authors.lastname: Huang
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors; D048728:MAP Kinase Kinase Kinase 1; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; C405053:L 783277; D007783:Lactones; D012118:Resorcinols; D000255:Adenosine Triphosphate; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human