title: 2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.
abstract: MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.
authors.affiliation: Abbott Laboratories, 100 Research Drive, Worcester, MA 01605-5314, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Argiriadi
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ericsson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Harris
authors.forename: David L
authors.initials: DL
authors.lastname: Banach
authors.forename: David W
authors.initials: DW
authors.lastname: Borhani
authors.forename: David J
authors.initials: DJ
authors.lastname: Calderwood
authors.forename: Megan D
authors.initials: MD
authors.lastname: Demers
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dimauro
authors.forename: Richard W
authors.initials: RW
authors.lastname: Dixon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hardman
authors.forename: Silvia
authors.initials: S
authors.lastname: Kwak
authors.forename: Biqin
authors.initials: B
authors.lastname: Li
authors.forename: John A
authors.initials: JA
authors.lastname: Mankovich
authors.forename: Douglas
authors.initials: D
authors.lastname: Marcotte
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Mullen
authors.forename: Baofu
authors.initials: B
authors.lastname: Ni
authors.forename: M
authors.initials: M
authors.lastname: Pietras
authors.forename: Ramkrishna
authors.initials: R
authors.lastname: Sadhukhan
authors.forename: Silvino
authors.initials: S
authors.lastname: Sousa
authors.forename: Medha J
authors.initials: MJ
authors.lastname: Tomlinson
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Xiang
authors.forename: Robert V
authors.initials: RV
authors.lastname: Talanian
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D003198:Computer Simulation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000255:Adenosine Triphosphate; D000893:Anti-Inflammatory Agents; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D000099190:MAP-Kinase-Activated Kinase 2; C017205:2,4-diaminopyrimidine