Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series

Arthur Oubrie; Allard Kaptein; Edwin de Zwart; Niels Hoogenboom; Rianne Goorden; Bas van de Kar; Maaike van Hoek; Vera de Kimpe; Ruud van der Heijden; Judith Borsboom; Bert Kazemier; Jeroen de Roos; Michiel Scheffers; Jos Lommerse; Carsten Schultz-Fademrecht; Tjeerd Barf

doi:10.1016/j.bmcl.2011.10.071

Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series

Bioorg Med Chem Lett. 2012 Jan 1;22(1):613-8. doi: 10.1016/j.bmcl.2011.10.071. Epub 2011 Nov 3.

Authors

Arthur Oubrie¹, Allard Kaptein, Edwin de Zwart, Niels Hoogenboom, Rianne Goorden, Bas van de Kar, Maaike van Hoek, Vera de Kimpe, Ruud van der Heijden, Judith Borsboom, Bert Kazemier, Jeroen de Roos, Michiel Scheffers, Jos Lommerse, Carsten Schultz-Fademrecht, Tjeerd Barf

Affiliation

¹ Merck Research Laboratories, MSD, PO Box 20, 5340 BH Oss, The Netherlands.

PMID: 22119462
DOI: 10.1016/j.bmcl.2011.10.071

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.

MeSH terms

Benzamides / pharmacology*
Chemistry, Pharmaceutical / methods*
Computer Simulation
Crystallography, X-Ray / methods
Cytokines / metabolism
Drug Design
HSP27 Heat-Shock Proteins / metabolism
Heat-Shock Proteins
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / pharmacology*
Models, Chemical
Molecular Chaperones
Phosphorylation
Piperidones / pharmacology*
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / pharmacology*
Pyrroles / chemistry
Tumor Necrosis Factor-alpha / metabolism*

Substances

Benzamides
Cytokines
HSP27 Heat-Shock Proteins
HSPB1 protein, human
Heat-Shock Proteins
Intracellular Signaling Peptides and Proteins
Molecular Chaperones
Piperidones
Protein Kinase Inhibitors
Pyrroles
Tumor Necrosis Factor-alpha
MAP-kinase-activated kinase 2
Protein Serine-Threonine Kinases