Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3).

Autor:	Kaniskan HÜ; Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States., Eram MS; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada., Zhao K; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Szewczyk MM; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada., Yang X; Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States., Schmidt K; Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States., Luo X; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Xiao S; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Dai M; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., He F; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Zang I; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Lin Y; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Li F; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada., Dobrovetsky E; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada., Smil D; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada., Min SJ; Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States., Lin-Jones J; DiscoveRx Corporation , Fremont, California 94538, United States., Schapira M; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.; Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada., Atadja P; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Li E; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada., Arrowsmith CH; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.; Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre , 101 College Street, MaRS South Tower, Suite 707, Toronto, ON M5G 1L7, Canada., Brown PJ; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada., Liu F; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China., Yu Z; Novartis Institutes for Biomedical Research (China), Zhangjiang Hi-Tech Park , Pudong New Area, Shanghai 201203, China., Vedadi M; Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.; Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada., Jin J; Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Feb 08; Vol. 61 (3), pp. 1204-1217. Date of Electronic Publication: 2018 Jan 05.
DOI:	10.1021/acs.jmedchem.7b01674
Abstrakt:	PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure-activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC 50 values: ∼10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.
Databáze:	MEDLINE
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