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Protein arginine methylation is aposttranslational modificationcritical for a variety of biological processes. Misregulation of proteinarginine methyltransferases (PRMTs) has been linked to many pathologicalconditions. Most current PRMT inhibitors display limited specificityand selectivity, indiscriminately targeting many methyltransferaseenzymes that use S-adenosyl-l-methionineas a cofactor. Here we report diamidine compounds for specific inhibitionof PRMT1, the primary type I enzyme. Docking, molecular dynamics,and MM/PBSA analysis together with biochemical assays were conductedto understand the binding modes of these inhibitors and the molecularbasis of selective inhibition for PRMT1. Our data suggest that 2,5-bis(4-amidinophenyl)furan(1, furamidine, DB75), one leading inhibitor, targetsthe enzyme active site and is primarily competitive with the substrateand noncompetitive toward the cofactor. Furthermore, cellular studiesrevealed that 1is cell membrane permeable and effectivelyinhibits intracellular PRMT1 activity and blocks cell proliferationin leukemia cell lines with different genetic lesions. [ABSTRACT FROM AUTHOR]