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Cited by 197Protein Kinase Regulation and GTPase SignalingCancer-related gene regulationCancer, Lipids, and Metabolism

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

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Winter-Vann, Ann M., Baron, Rudi A., Wong, Waihay, dela Cruz, June, York, John D., Gooden, David M., Bergo, Martin O., Young, Stephen G. +2 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0408107102PMC PMC555472
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Abstract

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-1 H -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.

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  • Cysmethynil, a small molecule inhibitor of ICMT, disrupts RAS membrane binding and reduces cell growth in RAS mutant cell lines.

    “Cysmethynil, a small molecule inhibitor of ICMT, disrupts RAS membrane binding and reduces cell growth in RAS mutant cell lines [46–48].”

    From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [46]

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Authors
Winter-Vann, A. M., Baron, R. A., Wong, W., dela Cruz, J., York, J. D., Gooden, D. M., Bergo, M. O., Young, S. G., Toone, E. J., & Casey, P. J.
Affiliations
  • University of California, Los Angeles (US)
  • Departments of Pharmacology and Cancer Biology and Chemistry, Duke University Medical Center, Durham, NC 27710; Department of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden; and Department of Medicine, University of California, Los Angeles, CA 90095
Corresponding author
Casey, Patrick J.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-03-22
Volume
102
Issue
12
Pages
4336-4341
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0408107102
PMC
PMC555472
OpenAlex
W2001255466
Cited by
178
References
41
Citations by year
2026: 1 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 7 · 2017: 11 · 2016: 5 · 2015: 6 · 2014: 7 · 2013: 8 · 2012: 6
FWCI
4.66
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancerfonden
  • Vetenskapsrådet
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL076839, HL076839)
  • National Institute of General Medical Sciences (GM46372, R01GM046372)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050200, AR 050200)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
isoprenylcysteine carboxyl methyltransferase, prenylation, Ras GTPase, protein prenylation, EGF signaling, anchorage-independent growth, colon cancer, anticancer drug development, small molecule inhibitors
MeSH terms
Acetamides, Animals, Antineoplastic Agents, Cell Division, Cell Line, Cell Transformation, Neoplastic, Colonic Neoplasms, Dogs, Enzyme Inhibitors, Humans, Phenotype, Protein Methyltransferases, Recombinant Fusion Proteins, ras Proteins, Cell Line, Tumor, Mice

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