Structure-based lead identification of ATP-competitive MK2 inhibitors

MK2 kinase is a promising drug discovery target for the treatment of inflammatory diseases. Here, we describe the discovery of novel MK2 inhibitors using X-ray crystallography and structure-based drug design. The lead has in vivo efficacy in a short-term preclinical model.

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (12), p.3818-3822
Main Authors: Barf, Tjeerd, Kaptein, Allard, Wilde, Sander de, Heijden, Ruud van der, Someren, Richard van, Demont, Dennis, Schultz-Fademrecht, Carsten, Versteegh, Judith, Zeeland, Mario van, Seegers, Nicole, Kazemier, Bert, Kar, Bas van de, Hoek, Maaike van, Roos, Jeroen de, Klop, Henri, Smeets, Ruben, Hofstra, Claudia, Hornberg, Jorrit, Oubrie, Arthur
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Animals
Anti-TNFα
Binding, Competitive
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Caco-2 Cells
Crystallography, X-Ray
Disease Models, Animal
Drug Design
Humans
Inhibitory Concentration 50
Intracellular Signaling Peptides and Proteins - antagonists & inhibitors
Intracellular Signaling Peptides and Proteins - chemistry
MAPKAPK2
Medical sciences
MK2
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - chemistry
Rats
Rheumatoid arthritis
SBDD
Structure-Activity Relationship
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Description
Summary:MK2 kinase is a promising drug discovery target for the treatment of inflammatory diseases. Here, we describe the discovery of novel MK2 inhibitors using X-ray crystallography and structure-based drug design. The lead has in vivo efficacy in a short-term preclinical model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.04.018