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

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.

• Authors: Lakshmi Prabhu, Han Wei, Lan Chen, Özlem Demir, George Sandusky, Emily Sun, John Wang, Jessica Mo, Lifan Zeng, Melissa Fishel, Ahmad Safa, Rommie Amaro, Murray Korc, Zhong-Yin Zhang, Tao Lu
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 25 Pg. 39963-39977 (Jun 20 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28591716 (Publication Type: Journal Article)

Chemical References

• Amines
• Enzyme Inhibitors
• Hydrocarbons, Aromatic
• PR5-LL-CM01
• Purines
• Small Molecule Libraries
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Amines (chemistry, pharmacology)
• Animals
• Carcinoma, Pancreatic Ductal (drug therapy, enzymology, pathology)
• Cell Line
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, enzymology, pathology)
• Drug Screening Assays, Antitumor (methods)
• Enzyme Inhibitors (chemistry, pharmacology)
• HCT116 Cells
• HT29 Cells
• Humans
• Hydrocarbons, Aromatic (chemistry, pharmacology)
• Male
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Pancreatic Neoplasms (drug therapy, enzymology, pathology)
• Protein-Arginine N-Methyltransferases (antagonists & inhibitors, genetics, metabolism)
• Purines (chemistry, pharmacology)
• Small Molecule Libraries (chemistry, pharmacology)
• Treatment Outcome
• Xenograft Model Antitumor Assays