Inhibitors of Eukaryotic Translational Machinery as Therapeutic Agents

Abstract

Inhibiting eukaryotic protein translation with small molecules is emerging as a powerful therapeutic strategy. The advantage of targeting cellular translational machinery is that it is required for the highly proliferative state of many neoplastic cells, replication of certain viruses, and ultimately the expression of a wide variety of protein targets. Although, this approach has been exploited to develop clinical agents, such as homoharringtonine (HHT, 1), used to treat chronic myeloid leukemia (CML), inhibiting components of the translational machinery is often associated with cytotoxic phenotypes. However, recent studies have demonstrated that certain small molecules can inhibit the translation of specific subsets of proteins, leading to lower cytotoxicity, and opening-up therapeutic opportunities for translation inhibitors to be deployed in indications beyond oncology and infectious disease. This review summarizes efforts to develop inhibitors of the eukaryotic translational machinery as therapeutic agents and highlights emerging opportunities for translation inhibitors in the future.

Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action

“…The 5-position of quinoline was immediately ruled out as 4 showed a large drop in potency. Functionalizing the 6-position of the quinoline with a chlorine (6) or iodine (7) substituent, possibly due to unfavorable atomic size. Analogues with fluorine (8), chlorine (9), and bromine (10) substitutions to the 7-position of quinoline displayed moderate potency, with 9 performing the best in the ATPase assay of any inhibitor produced.…”

“…Conversely, translation of many non-oncogenic genes is cap-independent . Targeting specific cap-dependent translation factors that are altered in expression or activity in human cancers and not involved in translation of non-oncogenic housekeeping genes offers great promise for the development of a new generation of cancer therapeutics. , …”

“…5 Targeting specific cap-dependent translation factors that are altered in expression or activity in human cancers and not involved in translation of non-oncogenic housekeeping genes offers great promise for the development of a new generation of cancer therapeutics. 6,7 Cap-dependent translation is driven by the heterotrimeric eukaryotic initiation factor (eIF)4F complex, which catalyzes ribosome recruitment to mRNA and comprises eIF4G, eIF4E, and eIF4A. eIF4G is a scaffolding protein that positions eIF4F for heterotrimeric engagement and initiation factor-RNA binding, eIF4E binds the m 7 G mRNA cap, and eIF4A is the enzymatic driver of the complex.…”

Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumor eEF1A antagonist SR-A3

“…Bacterial ribosomes have long been targeted by small-molecule antimicrobials, 1 while the human ribosome and translation factors have recently emerged as promising drug targets for cancer and viral infections. 2,3 Eukaryotic elongation factor-1α (eEF1A) is an essential component of the translation machinery. 4 GTP-bound eEF1A delivers aminoacyl-transfer RNAs (aa-tRNA) to the ribosomal A site during the elongation phase of protein synthesis.…”

Cellular delivery of dinucleotides by conjugation with small molecules: targeting translation initiation for anticancer applications

“…23 Therefore, various therapeutic strategies for targeting eIF4E have been proposed to combat carcinogenesis. 24,25 These include antisense oligonucleotides and siRNAs to modulate eIF4E mRNA levels, 26,27 aptamers which target eIF4E, 28,29 and small molecules to disrupt the stability of the eIF4F complex either by preventing eIF4E binding to the mRNA 5 0 cap or by hindering association of eIF4E with the eIF4G scaffold protein. 30,31 Synthetic cap analogs have been studied as potential eIF4E antagonists for nearly three decades, 32 but their activity was limited by poor cell permeability.…”