CP-225,917 and CP-263,114, novel Ras farnesylation inhibitors from an unidentified fungus. I. Taxonomy, fermentation, isolation, and biochemical properties.
During the course of our screening for squalene synthase inhibitors and Ras farnesylation inhibitors, a novel fungal culture was discovered to produce two structurally unique compounds, CP-225,917 and CP-263,114, as well as zaragozic acid A (squalestatin I). The two compounds are characterized by a bicyclo[4.3.1]dec-1,6-diene core plus two extended alkyl chains. CP-225,917 and CP-263,114 inhibit Ras farnesyl transferase from rat brain with IC50 values of 6 microM and 20 microM, respectively. CP-225,917 inhibits squalene synthase with an IC50 value of 43 microM and CP-263,114 with an IC50 of 160 microM. The producing organism, though not fully classified, exhibits the characteristics of a sterile Phoma species.
Dabrah
T T
TT
Pfizer Central Research, Groton, CT 06340, USA.
Harwood
H J
HJ
Huang
L H
LH
Jankovich
N D
ND
Kaneko
T
T
Li
J C
JC
Lindsey
S
S
Moshier
P M
PM
Subashi
T A
TA
Therrien
M
M
Watts
P C
PC
D019883:Alkyl and Aryl Transferases; D000818:Animals; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D005285:Fermentation; D005658:Fungi / Q000145:classification* / Q000378:metabolism; D008299:Maleic Anhydrides / Q000302:isolation & purification* / Q000494:pharmacology; D051381:Rats; D014166:Transferases / Q000037:antagonists & inhibitors*
C104959:CP 225917; C104957:CP 263114; D004791:Enzyme Inhibitors; D008299:Maleic Anhydrides; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D013186:Farnesyl-Diphosphate Farnesyltransferase