Potent and selective farnesyl transferase inhibitors.
We recently described a novel series of CA(1)A(2)X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A(1)A(2) residue. Extensive exploration of structure--activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC(50) = 4.60 nM on isolated enzyme, EC(50) = 20.0 nM for growth inhibition on a tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.
Millet
Régis
R
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Université de Lille 2, BP 83 rue du Professeur Laguesse, 59006 Lille, France.
Domarkas
Juozas
J
Houssin
Raymond
R
Gilleron
Pauline
P
Goossens
Jean-François
JF
Chavatte
Philippe
P
Logé
Cédric
C
Pommery
Nicole
N
Pommery
Jean
J
Hénichart
Jean-Pierre
JP
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase