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

Publication ,  Journal Article
Fletcher, S; Keaney, EP; Cummings, CG; Blaskovich, MA; Hast, MA; Glenn, MP; Chang, S-Y; Bucher, CJ; Floyd, RJ; Katt, WP; Gelb, MH; Beese, LS ...
Published in: J Med Chem
October 14, 2010

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.

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Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

October 14, 2010

Volume

53

Issue

19

Start / End Page

6867 / 6888

Location

United States

Related Subject Headings

  • Sulfonamides
  • Structure-Activity Relationship
  • Rats
  • Protein Binding
  • Plasmodium falciparum
  • Nitriles
  • Molecular Structure
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Humans
 

Citation

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Fletcher, S., Keaney, E. P., Cummings, C. G., Blaskovich, M. A., Hast, M. A., Glenn, M. P., … Hamilton, A. D. (2010). Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents. J Med Chem, 53(19), 6867–6888. https://doi.org/10.1021/jm1001748
Fletcher, Steven, Erin Pusateri Keaney, Christopher G. Cummings, Michelle A. Blaskovich, Michael A. Hast, Matthew P. Glenn, Sung-Youn Chang, et al. “Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.J Med Chem 53, no. 19 (October 14, 2010): 6867–88. https://doi.org/10.1021/jm1001748.
Fletcher S, Keaney EP, Cummings CG, Blaskovich MA, Hast MA, Glenn MP, et al. Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents. J Med Chem. 2010 Oct 14;53(19):6867–88.
Fletcher, Steven, et al. “Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.J Med Chem, vol. 53, no. 19, Oct. 2010, pp. 6867–88. Pubmed, doi:10.1021/jm1001748.
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. Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents. J Med Chem. 2010 Oct 14;53(19):6867–6888.
Journal cover image

Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

October 14, 2010

Volume

53

Issue

19

Start / End Page

6867 / 6888

Location

United States

Related Subject Headings

  • Sulfonamides
  • Structure-Activity Relationship
  • Rats
  • Protein Binding
  • Plasmodium falciparum
  • Nitriles
  • Molecular Structure
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Humans