Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase

Junko Ohkanda, Corey L. Strickland, Michelle A. Blaskovich, Dora Carrico, Jeffrey W. Lockman, Andreas Vogt, Cynthia J. Bucher, Jiazhi Sun, Yimin Qian, David Knowles, Erin E. Pusateri, Saïd M. Sebti, Andrew Hamilton

Research output: Contribution to journalArticle

Abstract

A series of imidazole-containing peptidomimetic PFTase inhibitors and their co-crystal structures bound to PFTase and FPP are reported. The structures reveal that the peptidomimetics adopt a similar conformation to that of the extended CVIM tetrapeptide, with the imidazole group coordinating to the catalytic zinc ion. Both mono- and bis-imidazole-containing derivatives, 13 and 16, showed remarkably high enzyme inhibition activity against PFTase in vitro with IC50 values of 0.86 and 1.7 nM, respectively. The peptidomimetics were also highly selective for PFTase over PGGTase-I both in vitro and in intact cells. In addition, peptidomimetics 13 and 16 were found to suppress tumor growth in nude mouse xenograft models with no gross toxicity at a daily dose of 25 mg kg-1.

Original languageEnglish (US)
Pages (from-to)482-492
Number of pages11
JournalOrganic and Biomolecular Chemistry
Volume4
Issue number3
DOIs
StatePublished - 2006

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Peptidomimetics
imidazoles
inhibitors
proteins
Enzyme inhibition
Heterografts
Nude Mice
toxicity
Inhibitory Concentration 50
mice
Toxicity
Conformations
enzymes
Zinc
Tumors
tumors
zinc
Crystal structure
Ions
Derivatives

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)

Cite this

Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase. / Ohkanda, Junko; Strickland, Corey L.; Blaskovich, Michelle A.; Carrico, Dora; Lockman, Jeffrey W.; Vogt, Andreas; Bucher, Cynthia J.; Sun, Jiazhi; Qian, Yimin; Knowles, David; Pusateri, Erin E.; Sebti, Saïd M.; Hamilton, Andrew.

In: Organic and Biomolecular Chemistry, Vol. 4, No. 3, 2006, p. 482-492.

Research output: Contribution to journalArticle

Ohkanda, J, Strickland, CL, Blaskovich, MA, Carrico, D, Lockman, JW, Vogt, A, Bucher, CJ, Sun, J, Qian, Y, Knowles, D, Pusateri, EE, Sebti, SM & Hamilton, A 2006, 'Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase', Organic and Biomolecular Chemistry, vol. 4, no. 3, pp. 482-492. https://doi.org/10.1039/b508184j
Ohkanda, Junko ; Strickland, Corey L. ; Blaskovich, Michelle A. ; Carrico, Dora ; Lockman, Jeffrey W. ; Vogt, Andreas ; Bucher, Cynthia J. ; Sun, Jiazhi ; Qian, Yimin ; Knowles, David ; Pusateri, Erin E. ; Sebti, Saïd M. ; Hamilton, Andrew. / Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase. In: Organic and Biomolecular Chemistry. 2006 ; Vol. 4, No. 3. pp. 482-492.
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