title: Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2.
abstract: A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Ramzi F
authors.initials: RF
authors.lastname: Sweis
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Algire
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada ; Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 2M9, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chiang
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: David
authors.initials: D
authors.lastname: Maag
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Bailin
authors.initials: B
authors.lastname: Shaw
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Nirupama B
authors.initials: NB
authors.lastname: Soni
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada ; Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: William N
authors.initials: WN
authors.lastname: Pappano
keywords: Epigenetics; H3K36; SMYD2; lysine; methyltransferase; p53