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 phenotype in several cancers

including pancreatic ductal adenocarcinoma (PDAC)

colorectal cancer (CRC)

and breast cancer (BC)

making PRMT5 an important target for cancer therapy. Previously

we showed that PRMT5-mediated methylation of the nuclear factor (NF)-κB

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 significant PRMT5-inhibitory activity

and their anti-tumor properties were validated using cancer phenotypic assays

in vitro

. Furthermore

PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-κB methylation and its subsequent activation upon drug treatment. Using

in silico

prediction

we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity. Finally

Clo and Can treatment 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.