Constrained analogs of KCVFM with improved inhibitory properties against farnesyl transferase

Constrained analogs of KCVFM, reported thus far as one of the most active peptidic inhibitors of farnesyl transferase, have been synthesized. Replacement of Val-Phe with Val-Tic and (N-Me)Val-Tic led to dramatically more active analogs possessing favored extended conformations. Based on molecular modelling studies the design and synthesis of various conformational probes to be substituted for Val and Phe led to a good correlation between the ratio of extended conformers and biological activity.