title: Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy.
abstract: Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays.
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Alder
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Martin
authors.initials: M
authors.lastname: Ambler
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Campbell
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Aurelie C
authors.initials: AC
authors.lastname: Champigny
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Deakin
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: John D
authors.initials: JD
authors.lastname: Harling
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Harris
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Tim
authors.initials: T
authors.lastname: Longstaff
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Sean
authors.initials: S
authors.lastname: Lynn
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Aoife C
authors.initials: AC
authors.lastname: Maxwell
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Mooney
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Callum
authors.initials: C
authors.lastname: Scullion
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Onkar M P
authors.initials: OM
authors.lastname: Singh
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Ian E D
authors.initials: IE
authors.lastname: Smith
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Donald O
authors.initials: DO
authors.lastname: Somers
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Tame
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Gareth
authors.initials: G
authors.lastname: Wayne
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline Pharmaceuticals , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: James M
authors.initials: JM
authors.lastname: Woolven
keywords: Interleukin-2 inducible tyrosine kinase; Itk; aminobenzothiazole; kinase inhibitors; kinase selectivity; template hopping