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Issue 1, 2021

Pharmacophore-based screening of diamidine small molecule inhibitors for protein arginine methyltransferases

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Abstract

Protein arginine methyltransferases (PRMTs) are essential epigenetic and post-translational regulators in eukaryotic organisms. Dysregulation of PRMTs is intimately related to multiple types of human diseases, particularly cancer. Based on the previously reported PRMT1 inhibitors bearing the diamidine pharmacophore, we performed virtual screening to identify additional amidine-associated structural analogs. Subsequent enzymatic tests and characterization led to the discovery of a top lead K313 (2-(4-((4-carbamimidoylphenyl)amino)phenyl)-1H-indole-6-carboximidamide), which possessed low-micromolar potency with biochemical IC50 of 2.6 μM for human PRMT1. Limited selectivity was observed over some other PRMT isoforms such as CARM1 and PRMT7. Molecular modeling and inhibition pattern studies suggest that K313 is a nonclassic noncompetitive inhibitor to PRMT1. K313 significantly inhibited cell proliferation and reduced the arginine asymmetric dimethylation level in the leukaemia cancer cells.

Graphical abstract: Pharmacophore-based screening of diamidine small molecule inhibitors for protein arginine methyltransferases

Supplementary files

Article information


Submitted
23 Jul 2020
Accepted
13 Sep 2020
First published
30 Sep 2020

RSC Med. Chem., 2021,12, 95-102
Article type
Research Article

Pharmacophore-based screening of diamidine small molecule inhibitors for protein arginine methyltransferases

K. Qian, C. Yan, H. Su, T. Dang, B. Zhou, Z. Wang, X. Zhao, I. Ivanov, M. Ho and Y. G. Zheng, RSC Med. Chem., 2021, 12, 95 DOI: 10.1039/D0MD00259C

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