Clavaric acid: a triterpenoid inhibitor of farnesyl-protein transferase from Clavariadelphus truncatus.
Farnesyl-protein transferase (FPTase) catalyses the specific transfer of farnesyl to Ras-peptides that is essential for oncogenic activity in oncogene-mediated tumors. Specific inhibition of FPTase activity has been shown to reduce tumor development in nude mice challenged with oncogenic forms of ras, thereby establishing FPTase as a viable therapeutic target. Our continued efforts to discover inhibitors of FPTase has led to the discovery of a triterpenoidal inhibitor, clavaric acid (1). This compound inhibits rHFPTase with an IC50 value of 1.3 microM. Structure elucidation, structure modifications, and biological activity of clavaric acid are herein described.
Jayasuriya
H
H
Natural Products Drug Discovery, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
Silverman
K C
KC
Zink
D L
DL
Jenkins
R G
RG
Sanchez
M
M
Pelaez
F
F
Vilella
D
D
Lingham
R B
RB
Singh
S B
SB
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001487:Basidiomycota / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D005285:Fermentation; D006868:Hydrolysis; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D008745:Methylation; D051379:Mice; D013055:Spectrophotometry, Infrared
D004791:Enzyme Inhibitors; C115583:clavaric acid; D007810:Lanosterol; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase