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

A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by “piggy-backing” on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally...

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Veröffentlicht in:Journal of medicinal chemistry 2010-10, Vol.53 (19), p.6867-6888
Hauptverfasser: Fletcher, Steven, Keaney, Erin Pusateri, Cummings, Christopher G, Blaskovich, Michelle A, Hast, Michael A, Glenn, Matthew P, Chang, Sung-Youn, Bucher, Cynthia J, Floyd, Ryan J, Katt, William P, Gelb, Michael H, Van Voorhis, Wesley C, Beese, Lorena S, Sebti, Said M, Hamilton, Andrew D
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Sprache:eng
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Zusammenfassung:A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by “piggy-backing” on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure−activity relationship (SAR) study reported herein. Our most potent inhibitor is compound 1f, 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-I). A crystal structure of inhibitor 1a co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of 1a is stabilized by a π−π stacking interaction with the Y361β residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm1001748