Anticancer Small-Molecule Agents Targeting Eukaryotic Elongation Factor 1A: State of the Art

Abstract

Eukaryotic elongation factor 1A (eEF1A) canonically delivers amino acyl tRNA to the ribosomal A site during the elongation stage of protein biosynthesis. Yet paradoxically, the oncogenic nature of this instrumental protein has long been recognized. Consistently, eEF1A has proven to be targeted by a wide assortment of small molecules with excellent anticancer activity, among which plitidepsin has been granted approval for the treatment of multiple myeloma. Meanwhile, metarrestin is currently under clinical development for metastatic cancers. Bearing these exciting advances in mind, it would be desirable to present a systematic up-to-date account of the title topic, which, to the best of our knowledge, has thus far been unavailable in the literature. The present review summarizes recent advances in eEF1A-targeting anticancer agents, both naturally occurring and synthetically crafted, with regard to their discovery or design, target identification, structure–activity relationship, and mode of action. Their structural diversity and differential eEF1A-targeting mechanisms warrant continuing research in pursuit of curing eEF1A-driven malignancy.

Heck Macrocyclization in Forging Non-Natural Large Rings including Macrocyclic Drugs

“…To our satisfaction, the precursor 55 underwent smooth ring closure in a 70% yield under Heck coupling conditions, TBS deprotection then furnishing 57 ready for divergent post-macrocyclization esterification (Figure 8B) [90]. Although nannocystin A was shown to be a specific inhibitor of eukaryotic elongation factor 1A (eEF1A) [91], its exact anticancer mode of action awaits further elucidation [92]. Informed by thus obtained SAR and pursuing a nannocystin-based fluorescent probe [93], we designed and synthesized a coumarin conjugate 58 with good cell permeability.…”

Editorial for the Special Issue—“Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies”

“…In addition to these original research manuscripts, three review articles were published in this Special Issue. One of them was provided by Zhang et al, which also deals with a promising target of the cellular translation machinery, the eukaryotic elongation factor 1A (eEF1A) [8]. Among the described eEF1A inhibitors, plitidepsin is already approved for multiple myeloma treatment, and another compound (metarrestin) is currently in clinical trials.…”