title: CP-225,917 and CP-263,114, novel Ras farnesylation inhibitors from an unidentified fungus. I. Taxonomy, fermentation, isolation, and biochemical properties.
abstract: 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.
authors.affiliation: Pfizer Central Research, Groton, CT 06340, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Dabrah
authors.forename: H J
authors.initials: HJ
authors.lastname: Harwood
authors.forename: L H
authors.initials: LH
authors.lastname: Huang
authors.forename: N D
authors.initials: ND
authors.lastname: Jankovich
authors.forename: T
authors.initials: T
authors.lastname: Kaneko
authors.forename: J C
authors.initials: JC
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Lindsey
authors.forename: P M
authors.initials: PM
authors.lastname: Moshier
authors.forename: T A
authors.initials: TA
authors.lastname: Subashi
authors.forename: M
authors.initials: M
authors.lastname: Therrien
authors.forename: P C
authors.initials: PC
authors.lastname: Watts
mesh_terms: 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*
chemical_list: 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