Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.

Journal Article (Journal Article)

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 IC(50) value of 25 nM and a whole cell H-Ras processing IC(50) 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.

Full Text

Duke Authors

Cited Authors

  • Fletcher, S; Keaney, EP; Cummings, CG; Blaskovich, MA; Hast, MA; Glenn, MP; Chang, S-Y; Bucher, CJ; Floyd, RJ; Katt, WP; Gelb, MH; Van Voorhis, WC; Beese, LS; Sebti, SM; Hamilton, AD

Published Date

  • October 14, 2010

Published In

Volume / Issue

  • 53 / 19

Start / End Page

  • 6867 - 6888

PubMed ID

  • 20822181

Pubmed Central ID

  • PMC3045627

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm1001748


  • eng

Conference Location

  • United States