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 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.
Zhao
A
A
Merck Research Laboratories, Rahway, NJ 07065, USA.
Lee
S H
SH
Mojena
M
M
Jenkins
R G
RG
Patrick
D R
DR
Huber
H E
HE
Goetz
M A
MA
Hensens
O D
OD
Zink
D L
DL
Vilella
D
D
Dombrowski
A W
AW
Lingham
R B
RB
Huang
L
L
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*
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