3vf8
Crystal Structure of Spleen Tyrosine Kinase Syk Catalytic Domain with Pyrazolylbenzimidazole Inhibitor 416Crystal Structure of Spleen Tyrosine Kinase Syk Catalytic Domain with Pyrazolylbenzimidazole Inhibitor 416
Structural highlights
Publication Abstract from PubMedBeginning 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. X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase.,McLean LR, Zhang Y, Zaidi N, Bi X, Wang R, Dharanipragada R, Jurcak JG, Gillespy TA, Zhao Z, Musick KY, Choi YM, Barrague M, Peppard J, Smicker M, Duguid M, Parkar A, Fordham J, Kominos D Bioorg Med Chem Lett. 2012 May 1;22(9):3296-300. Epub 2012 Mar 11. PMID:22464456[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||