title: Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design.
abstract: 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.
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. brian.cook@boehringer-ingelheim.com
authors.forename: Brian N
authors.initials: BN
authors.lastname: Cook
authors.forename: Jörg
authors.initials: J
authors.lastname: Bentzien
authors.forename: Andre
authors.initials: A
authors.lastname: White
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nemoto
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.forename: Chuk C
authors.initials: CC
authors.lastname: Man
authors.forename: Fariba
authors.initials: F
authors.lastname: Soleymanzadeh
authors.forename: Hnin Hnin
authors.initials: HH
authors.lastname: Khine
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: Stanley Z
authors.initials: SZ
authors.lastname: Kugler
authors.forename: John P
authors.initials: JP
authors.lastname: Wolak
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Roth
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Lombaert
authors.forename: Steven S
authors.initials: SS
authors.lastname: Pullen
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
mesh_terms: 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
chemical_list: 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