Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design.
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.
Cook
Brian N
BN
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. brian.cook@boehringer-ingelheim.com
Bentzien
Jörg
J
White
Andre
A
Nemoto
Peter A
PA
Wang
Ji
J
Man
Chuk C
CC
Soleymanzadeh
Fariba
F
Khine
Hnin Hnin
HH
Kashem
Mohammed A
MA
Kugler
Stanley Z
SZ
Wolak
John P
JP
Roth
Gregory P
GP
De Lombaert
Stéphane
S
Pullen
Steven S
SS
Takahashi
Hidenori
H
D020816:Amino Acid Motifs; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011725:Pyridines; C031000:benzimidazole; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; C023666:pyridine