title: Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK).
abstract: Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK. Electronic address: Giancarlo.Trani@evotec.com.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Trani
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Barker
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bromidge
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Brookfield
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: M Hicham A
authors.initials: MHA
authors.lastname: Ismaili
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Krülle
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Colin H
authors.initials: CH
authors.lastname: MacKinnon
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Maghames
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: McEwan
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Christian A G N
authors.initials: CAGN
authors.lastname: Montalbetti
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Pérez-Fuertes
authors.affiliation: Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
authors.forename: Darshan G
authors.initials: DG
authors.lastname: Vaidya
authors.affiliation: Discovery Biology, Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
authors.affiliation: Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013450:Sulfones; C031280:pyrazole; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; C023666:pyridine
keywords: ITK inhibitor; Sulfonylpyridine; T-cell receptor