title: Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series.
abstract: Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.
authors: Merck Research Laboratories, MSD, PO Box 20, 5340 BH Oss, The Netherlands.
authors: Arthur
authors: A
authors: Oubrie
authors: Allard
authors: A
authors: Kaptein
authors: Edwin
authors: E
authors: de Zwart
authors: Niels
authors: N
authors: Hoogenboom
authors: Rianne
authors: R
authors: Goorden
authors: Bas
authors: B
authors: van de Kar
authors: Maaike
authors: M
authors: van Hoek
authors: Vera
authors: V
authors: de Kimpe
authors: Ruud
authors: R
authors: van der Heijden
authors: Judith
authors: J
authors: Borsboom
authors: Bert
authors: B
authors: Kazemier
authors: Jeroen
authors: J
authors: de Roos
authors: Michiel
authors: M
authors: Scheffers
authors: Jos
authors: J
authors: Lommerse
authors: Carsten
authors: C
authors: Schultz-Fademrecht
authors: Tjeerd
authors: T
authors: Barf
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008956:Models, Chemical; D018832:Molecular Chaperones; D010766:Phosphorylation; D010881:Piperidones / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D001549:Benzamides; D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D010881:Piperidones; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2; C057725:HSPB1 protein, human