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Review
. 2018 Jun 1;10(6):a032995.
doi: 10.1101/cshperspect.a032995.

Therapeutic Opportunities in Eukaryotic Translation

Jennifer Chu  1 , Jerry Pelletier  1   2   3
Affiliations
Review

Therapeutic Opportunities in Eukaryotic Translation

Jennifer Chu et al. Cold Spring Harb Perspect Biol. .

Abstract

The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of translation. Small molecule inhibitors were instrumental in enabling investigators to capture short-lived complexes and characterize specific steps of protein synthesis. In addition, several drugs that are the mainstay of modern antimicrobial drug therapy are potent inhibitors of prokaryotic translation. Currently, there is much interest in targeting eukaryotic translation as decades of research have revealed that deregulated protein synthesis in cancer cells represents a targetable vulnerability. In addition to being potential therapeutics, small molecules that manipulate translation have also been shown to influence cognitive processes such as memory. In this review, we focus on small molecule modulators that target the eukaryotic translation initiation apparatus and provide an update on their potential application to the treatment of disease.

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Figures

Figure 1.
Figure 1.
Schematic diagram outlining the regulation of eIF4F assembly by mechanistic target of rapamycin (mTOR), eIF4E phosphorylation by MNK1/2, and messenger (mRNA) recruitment by eIF4F. The targets of known inhibitors are denoted. mTOR complex 1 (mTORC1) is a complex composed of mTOR, Raptor, MLST8, PRAS40, and DEPTOR and links nutrient/redox/energy levels to translation initiation.
Figure 2.
Figure 2.
Schematic diagram outlining the regulation of eIF2 recycling and the different steps known to be modulated by small molecules.
Figure 3.
Figure 3.
Small molecule inhibitors of eIF4E. (A) Interactions between m7GTP and eIF4E are denoted. (B) Chemical inhibitors of eIF4E:cap interaction. (C) Chemical inhibitors of eIF4E:eIF4G interaction.
See this image and copyright information in PMC

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