Structure-Based Design and Synthesis of Potent, Ethylenediamine-Based, Mammalian Farnesyltransferase Inhibitors as Anticancer Agents

A potent class of anticancer. human farnesyltransferase (111:Tase) inhibitors has been identified by piggy-backing on potent, antimalarial inhibitors of Plosmodium falciparum farnesyltransferase (P/FTase). On the basis of a 4-Fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure activity relationship (SA R) study reported herein. Our most potent inhibitor is compound If, which exhibited an in vitro hFTase IC50 value of 25 nm and a whole cell H-Ras processing IC50 value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective For hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-l). A crystal structure of inhibitor la co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of la is stabilized by pi-pi stacking interaction with the Y361 beta residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.