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 information of ITK and structurally related kinases led to the identification of indolylindazole and indolylpyrazolopyridine compounds with low nanomolar ITK inhibition.
Herdemann
Matthias
M
Nycomed GmbH, Konstanz, Germany.
Heit
Isabelle
I
Bosch
Frank-Uwe
FU
Quintini
Gianluca
G
Scheipers
Claudia
C
Weber
Alexander
A
D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D007191:Indazoles; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase