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

Kun Qian; Chunli Yan; Hairui Su; Tran Dang; Bo Zhou; Zhenyu Wang; Xinyang Zhao; Ivaylo Ivanov; Meng-Chiao Ho; Y. George Zheng

doi:10.1039/D0MD00259C

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

Kun Qian,

^a Chunli Yan,^b Hairui Su,^c Tran Dang,^a Bo Zhou,^a Zhenyu Wang,^b Xinyang Zhao,^c Ivaylo Ivanov,^b Meng-Chiao Ho^d and Y. George Zheng

*^a

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* Corresponding authors

^a Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, USA
E-mail: yzheng@uga.edu
Tel: +(706) 542 0277

^b Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30302, USA

^c Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

^d Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan

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.

RSC Medicinal Chemistry

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

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

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