Farnesylated Proteins as Anticancer Drug Targets: From Laboratory to the Clinic

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Farnesylated Proteins as Anticancer Drug Targets: From Laboratory to the Clinic



Anti-Cancer Agents in Medicinal Chemistry, 4(2): 123-138.

Author(s): Patrizia Russo, Maura Loprevite, Alfredo Cesario and Andrea Ardizzoni.

Affiliation: Molecular Pathology SectionLaboratory of Experimental Oncology National Institute for Research onCancer Largo Rosanna Benzi 10, I-16132 Genova ITALY

Abstract

The knowledge that Ras was readily prenylated by protein FTase and that the inhibition of this reaction has the ability to revert the transformed phenotype, provided the rationale for the development of FTIs as anticancer drugs. Studies have shown that farnesylation of Ras is the first, obligatory first step in a series of post-translational modifications leading to membrane association, which, in turn, determines the switch from an inactive to an active Ras-GTP bound form. Based on the theorical assumption that preventing Ras farnesylation might result in the inhibition of Ras functions, a range of FTIs have been synthesized. Their biology is fascinating since after substantial investigation and their use in several phase II studies and at least two phase III trials, the exact mechanism of action remains unclear. FTIs can block the farnesylation of several additional proteins, such as RhoB, prelamins A and B, centromere proteins (CENP-E, CENP-F), etc. While the FTIs clearly do not or only partly target Ras, these agents appear to have clinical activity in leukemia and in some solid tumors regardless of their Ras mutational status. Although inhibition of FTase by these compounds has been well documented also in normal tissues, their toxic effects seem to be manageable. However, preliminary results of early Phase II-III studies suggest that the activity of FTIs, as a single-agent, is modest and generally lower than that obtained by standard cytotoxic drugs. Ongoing clinical studies are assessing the role of FTIs for early stage disease or in combination with cytotoxic agents or with other molecular targeted therapies for advanced stage tumors.

Keywords:

farnesyltransferase, farnesyltransferase inhibitors, ras, farnesylated proteins.



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Article Details

Volume: 4
Issue Number: 2
First Page: 123
Last Page: 138
Page Count: 16
DOI: 10.2174/1568011043482098
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