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 D. Hamilton

doi:10.1039/B508184J

Structure-based design of imidazole-containing peptidomimeticinhibitors of protein farnesyltransferase

Junko Ohkanda,^a Corey L. Strickland,^b Michelle A. Blaskovich,^c Dora Carrico,^a Jeffrey W. Lockman,^a Andreas Vogt,^e Cynthia J. Bucher,^c Jiazhi Sun,^c Yimin Qian,^a David Knowles,^d Erin E. Pusateri,^a Saïd M. Sebti^c and Andrew D. Hamilton*^a

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* Corresponding authors

^a Department of Chemistry, Yale University, PO Box 208107, New Haven, CT, USA
E-mail: andrew.hamilton@yale.edu

^b Structural Chemistry and Tumor Biology Departments, Schering-Plough Research Institute, 2015 Galloping Hill Road, K15-3-3855, Kenilworth, New Jersey, USA

^c Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Departments of Oncology and Biochemistry & Molecular Biology, University of South Florida, Tampa, USA

^d Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

^e Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA

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.

Organic & Biomolecular Chemistry

Structure-based design of imidazole-containing peptidomimeticinhibitors of protein farnesyltransferase

Abstract

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

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