title: Exploration of cyanine compounds as selective inhibitors of protein arginine methyltransferases: synthesis and biological evaluation.
abstract: Protein arginine methyltransferase 1 (PRMT1) is involved in many biological activities, such as gene transcription, signal transduction, and RNA processing. Overexpression of PRMT1 is related to cardiovascular diseases, kidney diseases, and cancers; therefore, selective PRMT1 inhibitors serve as chemical probes to investigate the biological function of PRMT1 and drug candidates for disease treatment. Our previous work found trimethine cyanine compounds that effectively inhibit PRMT1 activity. In our present study, we systematically investigated the structure-activity relationship of cyanine structures. A pentamethine compound, E-84 (compound 50), showed inhibition on PRMT1 at the micromolar level and 6- to 25-fold selectivity over CARM1, PRMT5, and PRMT8. The cellular activity suggests that compound 50 permeated the cellular membrane, inhibited cellular PRMT1 activity, and blocked leukemia cell proliferation. Additionally, our molecular docking study suggested compound 50 might act by occupying the cofactor binding site, which provided a roadmap to guide further optimization of this lead compound.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Eric A
authors.initials: EA
authors.lastname: Owens
authors.forename: Hairui
authors.initials: H
authors.lastname: Su
authors.forename: Leilei
authors.initials: L
authors.lastname: Yan
authors.forename: Andrew
authors.initials: A
authors.lastname: Levitz
authors.forename: Xinyang
authors.initials: X
authors.lastname: Zhao
authors.forename: Maged
authors.initials: M
authors.lastname: Henary
authors.forename: Yujun George
authors.initials: YG
authors.lastname: Zheng
mesh_terms: D002232:Carbocyanines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002232:Carbocyanines; D004791:Enzyme Inhibitors; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases