title: Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1).
abstract: Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κβ, β-catenin, E2F1 and steroid hormone receptor ERα. As a result, CARM1 is involved in transcriptional activation, cellular differentiation, cell cycle progression, RNA splicing and DNA damage response. It has been associated with several human cancers including breast, colon, prostate and lung cancers and thus, is a potential oncological target. Herein, we present the design and synthesis of a series of CARM1 inhibitors. Based on a fragment hit, we discovered compound9as a potent inhibitor that displayed selectivity for CARM1 over other PRMTs.
authors.affiliation: Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: H Ü
authors.initials: HÜ
authors.lastname: Kaniskan
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: M S
authors.initials: MS
authors.lastname: Eram
authors.affiliation: Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
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authors.initials: D
authors.lastname: Smil
authors.affiliation: Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: M L
authors.initials: ML
authors.lastname: Martini
authors.affiliation: Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Santhakumar
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: P J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Arrowsmith
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: J
authors.initials: J
authors.lastname: Jin