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 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

Chemistry

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	482-492
Number of pages	11
Journal	Organic and Biomolecular Chemistry
Volume	4
Issue number	3
DOIs	https://doi.org/10.1039/b508184j
State	Published - 2006

ASJC Scopus subject areas

Biochemistry
Physical and Theoretical Chemistry
Organic Chemistry

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Ohkanda, J., Strickland, C. L., Blaskovich, M. A., Carrico, D., Lockman, J. W., Vogt, A., Bucher, C. J., Sun, J., Qian, Y., Knowles, D., Pusateri, E. E., Sebti, S. M., & Hamilton, A. D. (2006). Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase. Organic and Biomolecular Chemistry, 4(3), 482-492. https://doi.org/10.1039/b508184j

@article{9201b053963848bca7b000933c027dad,

title = "Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase",

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.",

author = "Junko Ohkanda and Strickland, {Corey L.} and Blaskovich, {Michelle A.} and Dora Carrico and Lockman, {Jeffrey W.} and Andreas Vogt and Bucher, {Cynthia J.} and Jiazhi Sun and Yimin Qian and David Knowles and Pusateri, {Erin E.} and Sebti, {Sa{\"i}d M.} and Hamilton, {Andrew D.}",

year = "2006",

doi = "10.1039/b508184j",

language = "English (US)",

volume = "4",

pages = "482--492",

journal = "Organic and Biomolecular Chemistry",

issn = "1477-0520",

publisher = "Royal Society of Chemistry",

number = "3",

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T1 - Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase

AU - Ohkanda, Junko

AU - Strickland, Corey L.

AU - Blaskovich, Michelle A.

AU - Carrico, Dora

AU - Lockman, Jeffrey W.

AU - Vogt, Andreas

AU - Bucher, Cynthia J.

AU - Sun, Jiazhi

AU - Qian, Yimin

AU - Knowles, David

AU - Pusateri, Erin E.

AU - Sebti, Saïd M.

AU - Hamilton, Andrew D.

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

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U2 - 10.1039/b508184j

DO - 10.1039/b508184j

M3 - Article

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AN - SCOPUS:33645234707

SN - 1477-0520

VL - 4

SP - 482

EP - 492

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

IS - 3

ER -

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

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