Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers

// Lakshmi Prabhu 1 , Han Wei 1 , Lan Chen 2,3,4 , Ozlem Demir 5 , George Sandusky 6 , Emily Sun 1 , John Wang 1 , Jessica Mo 1 , Lifan Zeng 2,3 , Melissa Fishel 9 , Ahmad Safa 1 , Rommie Amaro 5 , Murray Korc 7 , Zhong-Yin Zhang 3,4 and Tao Lu 1,3,8 1 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA 2 Chemical Genomics Core Facility, Indiana University School of Medicine, Indianapolis, IN, USA 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA 4 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA 5 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA 6 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 7 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 8 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA 9 Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA Correspondence to: Tao Lu, email: // Keywords : AlphaLISA, colorectal cancer, pancreatic ductal adenocarcinoma, PRMT5, small-molecule inhibitor Received : December 02, 2016 Accepted : April 28, 2017 Published : May 23, 2017 Abstract Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.