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

Matthias Herdemann; Isabelle Heit; Frank-Uwe Bosch; Gianluca Quintini; Claudia Scheipers; Alexander Weber

doi:10.1016/j.bmcl.2010.09.119

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

Bioorg Med Chem Lett. 2010 Dec 1;20(23):6998-7003. doi: 10.1016/j.bmcl.2010.09.119. Epub 2010 Sep 29.

Authors

Matthias Herdemann¹, Isabelle Heit, Frank-Uwe Bosch, Gianluca Quintini, Claudia Scheipers, Alexander Weber

Affiliation

¹ Nycomed GmbH, Konstanz, Germany.

PMID: 20965724
DOI: 10.1016/j.bmcl.2010.09.119

Abstract

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.

MeSH terms

Animals
Crystallography, X-Ray
Drug Design*
Humans
Indazoles / pharmacology
Interleukin-2
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

Substances

Indazoles
Interleukin-2
Protein Kinase Inhibitors
Pyridines
Small Molecule Libraries
Protein-Tyrosine Kinases
emt protein-tyrosine kinase