title: Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.
abstract: Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Eggert
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Roman C
authors.initials: RC
authors.lastname: Hillig
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Koehr
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Stöckigt
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Weiske
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Naomi
authors.initials: N
authors.lastname: Barak
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Mowat
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brumby
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Clara D
authors.initials: CD
authors.lastname: Christ
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Antonius
authors.initials: A
authors.lastname: Ter Laak
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Lang
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Amaury E
authors.initials: AE
authors.lastname: Fernandez-Montalvan
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Badock
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Hilmar
authors.initials: H
authors.lastname: Weinmann
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Ingo V
authors.initials: IV
authors.lastname: Hartung
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szewczyk
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Vijayaratnam
authors.initials: V
authors.lastname: Santhakumar
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: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Stellfeld
authors.affiliation: Drug Discovery, BAYER Pharma AG , Muellerstrasse 178, 13353 Berlin, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Stresemann
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D016159:Tumor Suppressor Protein p53; C513630:aminopyridazine; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human