Identification of potent ITK inhibitors through focused compound library design including structural information

A series of novel compound libraries inhibiting interleukin-2 inducible T cell kinase (ITK) were designed, synthesized and evaluated. In the first design cycle two library scaffolds were identified showing low micromolar inhibition of ITK. Further iterative design cycles including crystal structure...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 20; no. 23; pp. 6998 - 7003
Main Authors:	Herdemann, Matthias, Heit, Isabelle, Bosch, Frank-Uwe, Quintini, Gianluca, Scheipers, Claudia, Weber, Alexander
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 01-12-2010 Elsevier
Subjects:	Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Crystal structure Crystallography, X-Ray Docking Drug Design Focused kinase library Humans Indazoles - pharmacology Interleukin-2 Interleukin-2 inducible T cell kinase ITK ITK inhibitors Kinases Lead finding Lead optimisation Library design Ligand efficiency Medical sciences Pharmacology. Drug treatments Protein Kinase Inhibitors - analogs & derivatives Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-Tyrosine Kinases - antagonists & inhibitors Pyridines - pharmacology Small Molecule Libraries Structure-Activity Relationship X-ray ITK Focused kinase library Interleukin-2 inducible T cell kinase Kinases ITK inhibitors Lead finding Library design Docking Ligand efficiency Drug design X-ray Crystal structure Lead optimisation Ligand Selectivity Modeling Optimization Signal transduction Structure activity relation Chemical compound library Molecular model Chemical synthesis Enzyme Transferases Enzyme inhibitor Non-specific protein-tyrosine kinase Indazole derivatives Indole derivatives Crystalline structure
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Summary:	A series of novel compound libraries inhibiting interleukin-2 inducible T cell kinase (ITK) were designed, synthesized and evaluated. In the first design cycle two library scaffolds were identified showing low micromolar inhibition of ITK. Further iterative design cycles including crystal structure information of ITK and structurally related kinases led to the identification of indolylindazole and indolylpyrazolopyridine compounds with low nanomolar ITK inhibition.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.09.119