Targeting Prolyl-tRNA Synthetase to Control Cancer

Abstract

Lung cancer is the most common cancer in terms of both incidence and mortality. Despite intensive investigation, effective therapeutic target and reliable compounds are still limited. Here, I discovered bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) included in protein synthesis as a potential cancer target and its specific inhibitors using validated assay systems. EPRS is highly expressed in a variety of cancers including lung cancer and also involved in cancer metastasis and angiogenesis. Recently, halofuginone (HF) was identified as a compound binding with EPRS concomitant with inhibiting prolyl-tRNA synthetase (PRS) catalytic activity although HF has a poor drug-likeness and high cytotoxicity. In order to find novel compound which has improved druggability, I have screened PRS inhibitors using HF as a reference compound. Hundreds of compounds were synthesized by inherent synthetic strategy to maximize druggability and selected by analysis systems such as in vitro enzyme assay, proliferation, migration and cell death. Finally I identified effective 3 hit compounds controlling PRS catalytic activity as well as cell viability. Taken together, this study suggested the validation of anti-cancer targets and plausible anti-cancer therapeutic tools.