title: Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).
abstract: Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
authors.affiliation: Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, United Kingdom.
authors.forename: Colin H
authors.initials: CH
authors.lastname: MacKinnon
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Jonathon
authors.initials: J
authors.lastname: Dines
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.forename: Allan
authors.initials: A
authors.lastname: Jaochico
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Joachim
authors.initials: J
authors.lastname: Kraemer
authors.forename: Susanne
authors.initials: S
authors.lastname: Kruger
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Krülle
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.forename: Rosemary
authors.initials: R
authors.lastname: Maghames
authors.forename: Christian A G N
authors.initials: CA
authors.lastname: Montalbetti
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Pérez-Fuertes
authors.forename: Steven
authors.initials: S
authors.lastname: Shia
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stein
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Trani
authors.forename: Darshan G
authors.initials: DG
authors.lastname: Vaidya
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Wang
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; C005465:benzothiazole
keywords: Anti-inflammatory; Asthma; Benzothiazole; ITK inhibitor; SAR; TCR signalling