Therapeutic Opportunities in Eukaryotic Translation

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.

Fluorescent Turn‐On Probes for the Development of Binding and Hydrolytic Activity Assays for mRNA Cap‐Recognizing Proteins

“…The experiments were performed in 96-well, black, nonbinding assay plates. Each well contained appropriate buffer (50 mm Tris/HCl pH 7.6 containing 200 mm KCl and 0.5 mm EDTA), substrate (5 mm of probe 4b), enzyme (10 nm of DcpS dimer at 308), inhibitor (half log dilutions log C inh 2 < À2.5;2 > for m 7 GMP,m 7 GDP,m 7 GpNHp, m 7 GpCH 2 p, m 2 7,2'-O GpCH 2 pa nd m 7 GpCH 2 ppG or logC inh 2 < À3;1.5 > for m 7 GSpp S pSG D1, m 7 GSpp S pSG D2 and RG3039) and 10 nm of DcpS enzyme. During the experiment, point fluorescence detection (exc.…”

“…[4] eIF4E is required for cell growth [5] and its overexpression resultsi nl arge phenotypic changes, proliferation, and malignant transformation. [6][7][8] Elevated levels of eIF4E have been found in > 50 %t ypes of cancer, including breast, [9] larynx and hypopharynx, [10] and prostate [11] cancer. The oncogenic properties of eIF4E result from the fact that changes in eIF4E levels particularly strongly influence the translation of eIF4E-sensitive mRNAs (so-called "weak mRNAs"), which often encodet umor and survival-promoting proteins.…”

“…[18,19] Another cap-binding protein of therapeutic relevance is the decapping scavenger (DcpS)e nzyme, involved in 3'-to-5' mRNA degradation by exosomes, which releases nucleoside monophosphates (NMPs) and residual capped mono-or oligonucleotides. The residual cap structures are subsequently hydrolyzed by DcpS, which cleaves the pyrophosphate bond to releasem 7 GMP.I mportantly,D cpSh as been identified as am olecular target in spinal musculara trophy (SMA) and itsi nhibitors are potential therapeutics that could alleviateS MA symptoms. [20,21] C5-substitued quinazolines [20] have been reported as DcpS inhibitors, with the compound RG3039 and its analogues being among the most efficient.…”

“…Gp 5 Go rl og C inh 2 < À3;1.5 > for m7 GSpp S pSG D1, m 7 GSpp S pSG D2, RG3039 and m 7 Gp 4 )a nd protein (concentrations determined in Ta ble S4 and S7). The reaction components with added protein were preincubated for 15 min at 30 8Cw ith 300 rpm mixing.…”

A chemical screen identifies a link between lipid metabolism and mRNA translation

“…For instance, a number of oncogenes drive transcription of components of the translation machinery and the over-expression of translation initiation factors can facilitate oncogenic transformation (reviewed in (7,8)). In this context, several strategies have focused on lowering translation levels in cancer cells for oncological therapy (9). For example, chemical or genetic inhibition of the eIF4F complex involved in translational initiation has shown promising results in overcoming the resistance to various cancer therapies, and several compounds are in clinical trials as antineoplastic drugs (10).…”