The Journal of Antibiotics
Online ISSN : 1881-1469
Print ISSN : 0021-8820
ISSN-L : 0021-8820
Resorcylic Acid Lactones: Naturally Occurring Potent and Selective Inhibitors of MEK
ANNIE ZHAOSEOK H. LEEMARINA MOIENAROSALIND G. JENKINSDENIS R. PATRICKHANS E. HUBERMICHAEL A. GOETZOTTO D. HENSENSDEBORAH L. ZINKDOLORES VILELLAANNE W. DOMBROWSKIRUSSELL B. LINGHAMLEEYUAN HUANG
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1999 Volume 52 Issue 12 Pages 1086-1094

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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 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.

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