Optimisation of ITK inhibitors through successive iterative design cycles

Matthias Herdemann; Alexander Weber; Jérôme Jonveaux; Frank Schwoebel; Michael Stoeck; Isabelle Heit

doi:10.1016/j.bmcl.2011.01.035

Optimisation of ITK inhibitors through successive iterative design cycles

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1852-6. doi: 10.1016/j.bmcl.2011.01.035. Epub 2011 Jan 14.

Authors

Matthias Herdemann¹, Alexander Weber, Jérôme Jonveaux, Frank Schwoebel, Michael Stoeck, Isabelle Heit

Affiliation

¹ Nycomed GmbH, Konstanz, Germany.

PMID: 21316219
DOI: 10.1016/j.bmcl.2011.01.035

Abstract

Based on a hit cluster of compounds inhibiting interleukin-2 inducible T-cell kinase (ITK) in the submicromolar range a series of ITK inhibitor libraries were synthesized. Through iterative design cycles including kinase crystal structure information, indolylindazole libraries were identified which showed low nanomolar activity in enzymatic and cellular assays. The potential of these novel lead series was confirmed through in vivo tests in an anti-CD3-IL2 mouse model. The intravenous administration of highly potent ITK inhibitor 11o resulted in dose-dependent, efficient suppression of IL-2.

MeSH terms

Animals
Crystallography, X-Ray
Mice
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein-Tyrosine Kinases / antagonists & inhibitors*

Substances

Protein Kinase Inhibitors
Protein-Tyrosine Kinases
emt protein-tyrosine kinase