title: Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation.
abstract: Protein arginine methyltransferases (PRMTs) are proved to play vital roles in chromatin remodeling, RNA metabolism, and signal transduction. Aberrant regulation of PRMT activity is associated with various pathological states such as cancer and cardiovascular disorders. Development and application of small molecule PRMT inhibitors will provide new avenues for therapeutic discovery. The combination of pharmacophore-based virtual screening methods with radioactive methylation assays provided six hits identified as inhibitors against the predominant arginine methyltransferase PRMT1 within micromolar potency. Two potent compounds, A9 and A36, exhibited the inhibitory effect by directly targeting substrate H4 other than PRMT1 and displayed even higher inhibition activity than the well-known PRMT inhibitors AMI-1. A9 significantly inhibits proliferation of castrate-resistant prostate cancer cells. Together, A9 may be a potential inhibitor against advanced hormone-independent cancers, and the work will provide clues for the future development of specific compounds that block the interaction of PRMTs with their targets.
authors.affiliation: Department of Chemistry, Program of Molecular Basis of Diseases, Georgia State University, P.O. Box 4098, Atlanta, Georgia 30302, USA.
authors.forename: Juxian
authors.initials: J
authors.lastname: Wang
authors.forename: Limin
authors.initials: L
authors.lastname: Chen
authors.forename: Sarmistha Halder
authors.initials: SH
authors.lastname: Sinha
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Huifang
authors.initials: H
authors.lastname: Chai
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Muniyan
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chou
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.forename: Leilei
authors.initials: L
authors.lastname: Yan
authors.forename: You
authors.initials: Y
authors.lastname: Feng
authors.forename: Keqin Kathy
authors.initials: KK
authors.lastname: Li
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Yujun George
authors.initials: YG
authors.lastname: Zheng
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D008745:Methylation / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014584:User-Computer Interface; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors; D000099224:p300-CBP-Associated Factor
chemical_list: D001120:Arginine; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D011484:Protein-Arginine N-Methyltransferases; D054852:Small Molecule Libraries; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor