title: Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.
abstract: Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cowen
authors.forename: Daniel
authors.initials: D
authors.lastname: Russell
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Dakin
authors.forename: Huawei
authors.initials: H
authors.lastname: Chen
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Larsen
authors.forename: Robert
authors.initials: R
authors.lastname: Godin
authors.forename: Scott
authors.initials: S
authors.lastname: Throner
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zheng
authors.forename: Audrey
authors.initials: A
authors.lastname: Molina
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Wu
authors.forename: Tony
authors.initials: T
authors.lastname: Cheung
authors.affiliation: Structure and Biophysics, Discovery Sciences, AstraZeneca, Mereside , Alderley Park, Cheshire, SK10 4TG United Kingdom.
authors.forename: Tina
authors.initials: T
authors.lastname: Howard
authors.forename: Renee
authors.initials: R
authors.lastname: Garcia-Arenas
authors.forename: Nicholas
authors.initials: N
authors.lastname: Keen
authors.affiliation: Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University , Nashville, Tennessee 37232 United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Pendleton
authors.affiliation: Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University , Nashville, Tennessee 37232 United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
authors.forename: Andrew D
authors.identifier: 0000-0002-1018-9631
authors.initials: AD
authors.lastname: Ferguson
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human