Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue

Market drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Protein arginine methyltransferase 5 (PRMT5) overexpression has been linked to promoting the tumor pheno-type in several cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC), making PRMT5 an important target for cancer therapy. Previ-ously, we showed that PRMT5-mediated methylation of the nuclear factor (NF) -KB, partially contributes to its constitutive activation observed in cancers. In this study, we utilized an AlphaLISA-based high-throughput screening method adapted in our lab, and identified one FDA-approved drug, Candesartan cilexetil (Can, used in hypertension treatment) and one EMA-approved drug, Cloperastine hydrochloride (Clo, used in cough treatment) that had signif-icant PRMT5-inhibitory activity, and their anti-tumor properties were validated using cancer phenotypic assays in vitro. Furthermore, PRMT5 selective inhibition of methyltransferase ac-tivity was confirmed by reduction of both NF -KB methylation and its subsequent activation upon drug treatment. Using in silico prediction, we identified critical residues on PRMT5 tar-geted by these drugs that may interfere with its enzymatic activity. Finally, Clo and Can treat-ment have exhibited marked reduction in tumor growth in vivo. Overall, we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies. Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.(c) 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Automated summary

This study identified two FDA and EMA-approved drugs (Candesartan cilexetil and Cloperastine hydrochloride) with significant inhibitory activity against PRMT5, a gene associated with tumor growth, through high-throughput screening. The anti-tumor properties of these drugs were validated in vitro and in vivo, providing a basis for repurposing them as anti-PRMT5 cancer therapies, allowing for the quick and safe utilization of previously unknown PRMT5 inhibitors in clinical practice.