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A small-molecule in...
A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells
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Winter-Vann, A. M. (author)
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Baron, R. A. (author)
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Wong, W. (author)
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Dela Cruz, J. (author)
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York, J. D. (author)
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Gooden, D. M. (author)
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- Bergö, Martin, 1970 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för invärtesmedicin,Institute of Internal Medicine
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Young, S. G. (author)
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Toone, E. J. (author)
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Casey, P. J. (author)
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(creator_code:org_t)
- 2005
- 2005
- English.
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In: Proc Natl Acad Sci U S A. ; 102:12, s. 4336-4341
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https://gup.ub.gu.se...
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- RAS
- drug targeting
- ICMT
- genteknik
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Winter-Vann, A. ...
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Baron, R. A.
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Wong, W.
-
Dela Cruz, J.
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York, J. D.
-
Gooden, D. M.
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show more...
-
Bergö, Martin, 1 ...
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Young, S. G.
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Toone, E. J.
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Casey, P. J.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
- Proc Natl Acad S ...
- By the university
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University of Gothenburg