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

Steven Fletcher, Erin Pusateri Keaney, Christopher G. Cummings, Michelle A. Blaskovich, Michael A. Hast, Matthew P. Glenn, Sung Youn Chang, Cynthia J. Bucher, Ryan J. Floyd, William P. Katt, Michael H. Gelb, Wesley C. Van Voorhis, Lorena S. Beese, Said M. Sebti, Andrew D. Hamilton

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6867-6888
Number of pages22
JournalJournal of Medicinal Chemistry
Volume53
Issue number19
DOIs
StatePublished - Oct 14 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Fletcher, S., Keaney, E. P., Cummings, C. G., Blaskovich, M. A., Hast, M. A., Glenn, M. P., Chang, S. Y., Bucher, C. J., Floyd, R. J., Katt, W. P., Gelb, M. H., Van Voorhis, W. C., Beese, L. S., Sebti, S. M., & Hamilton, A. D. (2010). Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents. Journal of Medicinal Chemistry, 53(19), 6867-6888. https://doi.org/10.1021/jm1001748