LLY-283

Description: LLY-283 is the first potent and selective SAM-competitive chemical probe for PRMT5 (protein arginine methyltransferase 5). In a biochemical assay, LLY-283 inhibits the PRMT5 enzyme activity with an IC50 of 20 nM for methylation of an H4R3 derived peptide substrate, it exhibits more than 100-fold selectivity for PRMT5 than other histone methyltransferases and non-epigenetic targets. PRMTs binds to the lysine or arginine residues of substrate proteins via the substrate binding groove and SAM via the cofactor binding site. These two binding sites are linked by a narrow hydrophobic channel that brings the substrate and cofactor in close proximity to allow the transfer of the methyl group from the cofactor SAM to a lysine or arginine residue via an SN2 transition state.

References: Chem Rev. 2018 Feb 14; 118(3): 989–1068; ACS Med. Chem. Lett. (2018) DOI: 10.1021/acsmedchemlett.8b00014