Protein Arginine Methyltransferases Library

ChemDiv’s PRMT Inhibitors Library contains 31,000 compounds.

Protein methyltransferases (PMTs) is a diverse class of enzymes catalyzing methylation of side chain nitrogen atoms on lysine or arginine residues in specific sequences of target proteins. These enzymes are crucial in regulating gene transcription, particularly through the methylation of lysine or arginine residues within histone proteins in chromatin. Such modifications can lead to changes in chromatin structure that either activate or repress gene transcription. Dysregulation of certain PMTs has been linked to oncogenic roles in various human cancers. Over the past decade, considerable advancements have been made in the discovery and development of small-molecule inhibitors targeting cancer-associated PMTs, such as protein arginine methyltransferases (PRMTs). These compounds often act as competitive inhibitors by binding in the S-adenosylmethionine binding pocket of PMTs.[1]

Our database includes over 100 small molecule scaffolds with demonstrated affinity against PRMTs. The focused library was curated using a combination of privileged substructure searches, which covers the core-head containing analogues, and computational techniques like 2D-topological pharmacophore modeling, isosteric morphing, and structure similarity searching based on the Tanimoto coefficient. This approach also involved selecting a diverse subset of compounds to ensure a broad representation of potential inhibitors.

The PRMT inhibitors have emerged as promising therapeutic agents in drug discovery due to their role in modulating epigenetic mechanisms. Since PRMTs are involved in critical cellular processes such as gene transcription, RNA processing, and DNA repair, their inhibitors are being actively researched for their potential in treating a range of diseases, including cancer, cardiovascular diseases, and neurological disorders. The development of PRMT inhibitors is particularly focused on targeting aberrant methylation patterns associated with disease onset, providing a novel approach for the development of targeted therapies with high specificity and reduced risk of adverse effects.

[1] R. A. Copeland, “Protein methyltransferase inhibitors as precision cancer therapeutics: A decade of discovery,” Philos. Trans. R. Soc. B Biol. Sci., vol. 373, no. 1748, 2018, doi: 10.1098/rstb.2017.0080.