title: X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase.
abstract: Beginning with a screening hit, unique thienopyrazole-indole inhibitors of Itk (interleukin-2-inducible tyrosine kinase) were designed, synthesized, and crystallized in the target kinase. Although initial compounds were highly active in Itk, they were not selective. Increasing the steric bulk around a tertiary alcohol at the 5-indole position dramatically improved selectivity toward Lyk and Syk, but not Txk. Substitutions at the 3- and 4-indole positions gave less active compounds that remained poorly selective. A difluoromethyl substitution at the 5-position of the thienopyrazole led to a highly potent and selective compound. Phenyl at this position reduced activity and selectivity while pushing the side-chains of Lys-391 and Asp-500 away from the binding pocket. Novel and selective thienopyrazole inhibitors of Itk were designed as a result of combining structure-based design and medicinal chemistry.
authors.affiliation: Molecular Innovative Therapeutics, Sanofi US, 1041 Route 202/206 N, Bridgewater, NJ 08807, United States. Larry.McLean@sanofi.com
authors.forename: Larry R
authors.initials: LR
authors.lastname: McLean
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nisha
authors.initials: N
authors.lastname: Zaidi
authors.forename: Xiping
authors.initials: X
authors.lastname: Bi
authors.forename: Rachel
authors.initials: R
authors.lastname: Wang
authors.forename: Ram
authors.initials: R
authors.lastname: Dharanipragada
authors.forename: John G
authors.initials: JG
authors.lastname: Jurcak
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Gillespy
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Kwon Y
authors.initials: KY
authors.lastname: Musick
authors.forename: Yong-Mi
authors.initials: YM
authors.lastname: Choi
authors.forename: Matthieu
authors.initials: M
authors.lastname: Barrague
authors.forename: Jane
authors.initials: J
authors.lastname: Peppard
authors.forename: Matthew
authors.initials: M
authors.lastname: Smicker
authors.forename: Mei
authors.initials: M
authors.lastname: Duguid
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Parkar
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fordham
authors.forename: Dorothea
authors.initials: D
authors.lastname: Kominos
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase