A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells

Many key regulatory proteins, including members of the Ras family of GTPases, are modified at their C terminus by a process termed prenylation. This processing is initiated by the addition of an isoprenoid lipid, and the proteins are further modified by a proteolytic event and methylation of the C-t...

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Main Authors: Winter-Vann, Ann M., Baron, Rudi A., Wong, Waihay, dela Cruz, June, York, John D., Gooden, David M., Bergo, Martin O., Young, Stephen G., Toone, Eric J., Casey, Patrick J.
Formato: Artigo
Idioma:English
Publicado em: National Academy of Sciences 2005
Assuntos:
Biological Sciences
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC555472/
https://ncbi.nlm.nih.gov/pubmed/15784746
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1073/pnas.0408107102
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spelling pubmed-5554722005-09-22 A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells Winter-Vann, Ann M. Baron, Rudi A. Wong, Waihay dela Cruz, June York, John D. Gooden, David M. Bergo, Martin O. Young, Stephen G. Toone, Eric J. Casey, Patrick J. Proc Natl Acad Sci U S A Biological Sciences Many key regulatory proteins, including members of the Ras family of GTPases, are modified at their C terminus by a process termed prenylation. This processing is initiated by the addition of an isoprenoid lipid, and the proteins are further modified by a proteolytic event and methylation of the C-terminal prenylcysteine. Although the biological consequences of prenylation have been characterized extensively, the contributions of prenylcysteine methylation to the functions of the modified proteins are not well understood. This reaction is catalyzed by the enzyme isoprenylcysteine carboxyl methyltransferase (Icmt). Recent genetic disruption studies have provided strong evidence that blocking Icmt activity has profound consequences on oncogenic transformation. Here, we report the identification of a selective small-molecule inhibitor of Icmt, 2-[5-(3-methylphenyl)-1-octyl-1H-indol-3-yl]acetamide (cysmethynil). Cysmethynil treatment results in inhibition of cell growth in an Icmt-dependent fashion, demonstrating mechanism-based activity of the compound. Treatment of cancer cells with cysmethynil results in mislocalization of Ras and impaired epidermal growth factor signaling. In a human colon cancer cell line, cysmethynil treatment blocks anchorage-independent growth, and this effect is reversed by overexpression of Icmt. These findings provide a compelling rationale for development of Icmt inhibitors as another approach to anticancer drug development. National Academy of Sciences 2005-03-22 /pmc/articles/PMC555472/ /pubmed/15784746 http://dx.doi.org/10.1073/pnas.0408107102 Text en Copyright © 2005, The National Academy of Sciences
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Biological Sciences
spellingShingle Biological Sciences
Winter-Vann, Ann M.
Baron, Rudi A.
Wong, Waihay
dela Cruz, June
York, John D.
Gooden, David M.
Bergo, Martin O.
Young, Stephen G.
Toone, Eric J.
Casey, Patrick J.
A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
description Many key regulatory proteins, including members of the Ras family of GTPases, are modified at their C terminus by a process termed prenylation. This processing is initiated by the addition of an isoprenoid lipid, and the proteins are further modified by a proteolytic event and methylation of the C-terminal prenylcysteine. Although the biological consequences of prenylation have been characterized extensively, the contributions of prenylcysteine methylation to the functions of the modified proteins are not well understood. This reaction is catalyzed by the enzyme isoprenylcysteine carboxyl methyltransferase (Icmt). Recent genetic disruption studies have provided strong evidence that blocking Icmt activity has profound consequences on oncogenic transformation. Here, we report the identification of a selective small-molecule inhibitor of Icmt, 2-[5-(3-methylphenyl)-1-octyl-1H-indol-3-yl]acetamide (cysmethynil). Cysmethynil treatment results in inhibition of cell growth in an Icmt-dependent fashion, demonstrating mechanism-based activity of the compound. Treatment of cancer cells with cysmethynil results in mislocalization of Ras and impaired epidermal growth factor signaling. In a human colon cancer cell line, cysmethynil treatment blocks anchorage-independent growth, and this effect is reversed by overexpression of Icmt. These findings provide a compelling rationale for development of Icmt inhibitors as another approach to anticancer drug development.
author Winter-Vann, Ann M.
Baron, Rudi A.
Wong, Waihay
dela Cruz, June
York, John D.
Gooden, David M.
Bergo, Martin O.
Young, Stephen G.
Toone, Eric J.
Casey, Patrick J.
author_facet Winter-Vann, Ann M.
Baron, Rudi A.
Wong, Waihay
dela Cruz, June
York, John D.
Gooden, David M.
Bergo, Martin O.
Young, Stephen G.
Toone, Eric J.
Casey, Patrick J.
author_sort Winter-Vann, Ann M.
title A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
title_short A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
title_full A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
title_fullStr A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
title_full_unstemmed A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
title_sort small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
publisher National Academy of Sciences
publisher_facet National Academy of Sciences
publishDate 2005
url https://ncbi.nlm.nih.gov/pmc/articles/PMC555472/
https://ncbi.nlm.nih.gov/pubmed/15784746
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1073/pnas.0408107102
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