The United States Patent and Trademark Office has issued a patent to Cayman Chemical and the University of Michigan claiming novel reagents used for screening small-molecule chemical libraries for new drug leads. The reagents are fluorescent detection analytes that competitively bind to a key cofactor binding site of enzymes that catalyze methylation of histones, DNA, and RNA. These epigenetic modifications regulate gene expression, impacting normal growth as well as cancer and disease. Dysregulation of histone methylation patterns is observed in a variety of human cancers, inflammation, and neurodegenerative diseases, validating histone methyltransferases (HMTs) as an important class of drug targets among biomedical researchers.

The newly issued patent, US No. 9,120,820, claims detection analyte probes based on a natural product mimic of the methyltransferase cofactor S-adenosylmethionine (SAM). Aptly named SAM-Screener™, these probes are the foundation of Cayman’s high-throughput, one-step florescent binding assays for identification of SAM-competitive methyltransferase inhibitors from small-molecule chemical libraries.

“The SAM-Screener technology meets the currently unaddressed need for rapid and efficient screening of large compound libraries for SAM-competitive specific methyltransferase inhibitors. Other commercial assays do not distinguish between substrate-competitive and cofactor-competitive inhibitors,” said Stephen Barrett, Director of Drug Discovery Chemistry at Cayman Chemical. “We are going after drug compounds that have a specific mechanism of action and to identify them with that specific mechanism of action, unlike other HMT screening assays available.”

Raymond Trievel, Associate Professor of Biological Chemistry at the University of Michigan added, “The development of the SAM-Screener™ provides new chemical tools for studying substrate recognition by methyltransferases and offers a flexible platform for identifying SAM-competitive inhibitors, particularly for methyltransferases that are targets for the design of novel therapeutics to treat cancer and other diseases."

SAM-Screener assay kits are currently available for SET7/9, GLP, and MLL1 enzymes, with G9a and other SET domain methyltransferases currently in development. Custom assay development to adapt this assay format to other HMTs is also available through Cayman’s epigenetic screening and profiling service.

Cayman is poised to expand on the SAM-Screener™ technology with a patent pending second-generation SAM mimic-based probe designed to competitively bind to SAM-binding sites of a different set of methyltransferases. This probe will enable the screening of chemical libraries against a broader panel of target methyltransferase enzymes.