Virtual Screening and Biological Characterization of Novel Histone Arginine Methyltransferase PRMT1 Inhibitors

Abstract

Lysine and arginine methyltransferases participate in the posttranslational modification of histones and regulate key cellular functions. Protein arginine methyltransferase 1 (PRMT1) has been identified as an essential component of mixed lineage leukemia (MLL) oncogenic complexes, revealing its potential as a novel therapeutic target in human cancer. The first potent arginine methyltransferase inhibitors were recently discovered by random- and target-based screening approaches. Herein we report virtual and biological screening for novel inhibitors of PRMT1. Structure-based virtual screening (VS) of the Chembridge database composed of 328 000 molecules was performed with a combination of ligand- and target-based in silico approaches. Nine inhibitors were identified from the top-scored docking solutions; these were experimentally tested using human PRMT1 and an antibody-based assay with a time-resolved fluorescence readout. Among several aromatic amines, an aliphatic amine and an amide were also found to be active in the micromolar range.

The Emerging Therapeutic Potential of Histone Methyltransferase and Demethylase Inhibitors

“…Treatment of HepG2 cells resulted in a robust hypomethylation on histone H4 R3. [88] Based on the identified PRMT1 inhibitors stilbamidine and allantodapsone, Heinke et al [112] expanded their virtual and biological screening for novel inhibitors. Structure-based virtual screening of the Chembridge database comprising 328 000 molecules was performed by using a combination of ligandand target-based in silico screens.…”

Computer- and structure-based lead design for epigenetic targets

“…Based on the identified PRMT1 inhibitor 26, Heinke et al 101 expanded their virtual and biological screening for novel inhibitors. Structure-based VS of the Chembridge database comprising 328,000 molecules was performed using a combination of ligandand target-based in silico screening.…”

Small Molecule Inhibitors of Protein Arginine Methyltransferases

“…This compound inhibits cellular H4R3 methylation to the same level as AMI-1 at the same concentration in hepatocellular carcinoma cell line HepG2 while the H3K4 methylation level is barely impacted. Based on the pharmacophore of 3 , compounds 4 and 5 are discovered by the same group from another round of virtual screening and show about 1/10 of the potency of 3 [105]. Later, a series of compounds are explored based on the structure of 3 and 4 [71].…”