title: Optimisation of ITK inhibitors through successive iterative design cycles.
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.
authors.affiliation: Nycomed GmbH, Konstanz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Herdemann
authors.forename: Alexander
authors.initials: A
authors.lastname: Weber
authors.forename: Jérôme
authors.initials: J
authors.lastname: Jonveaux
authors.forename: Frank
authors.initials: F
authors.lastname: Schwoebel
authors.forename: Michael
authors.initials: M
authors.lastname: Stoeck
authors.forename: Isabelle
authors.initials: I
authors.lastname: Heit
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase