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. 2012 Apr 1;4(4):a012377.
doi: 10.1101/cshperspect.a012377.

Emerging therapeutics targeting mRNA translation

Abba Malina  1 , John R Mills, Jerry Pelletier
Affiliations

Emerging therapeutics targeting mRNA translation

Abba Malina et al. Cold Spring Harb Perspect Biol. .

Abstract

A defining feature of many cancers is deregulated translational control. Typically, this occurs at the level of recruitment of the 40S ribosomes to the 5'-cap of cellular messenger RNAs (mRNAs), the rate-limiting step of protein synthesis, which is controlled by the heterotrimeric eukaryotic initiation complex eIF4F. Thus, eIF4F in particular, and translation initiation in general, represent an exploitable vulnerability and unique opportunity for therapeutic intervention in many transformed cells. In this article, we discuss the development, mode of action and biological activity of a number of small-molecule inhibitors that interrupt PI3K/mTOR signaling control of eIF4F assembly, as well as compounds that more directly block eIF4F activity.

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Figures

Figure 1.
Figure 1.
Diagram illustrating rapamycin-resistance pathways. (A) Inhibition of mTORC1 by rapalogs leads to dampening of the S6K/IRS feedback loop (in gray box) and increased signaling flux to PI3K and Ras. (B) Increased levels of eIF4E can circumvent effects on cell proliferation and cell survival (in gray box) mediated by inhibition of mTORC1 by rapamycin. See text for details.
See this image and copyright information in PMC

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