X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase
| Autor: | Mei S. Duguid, Jurcak John G, Ram Dharanipragada, Rachel Wang, Matthew A. Smicker, Kwon Yon Musick, Xiping Bi, Ashfaq Parkar, Jane Peppard, Ying Zhang, Zhicheng Zhao, Nisha Zaidi, Choi Yong-Mi, Jeremy Fordham, Gillespy Timothy Alan, Dorothea Kominos, Matthieu Barrague, Larry R. McLean |
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| Rok vydání: | 2012 |
| Předmět: |
Steric effects
Interleukin 2 Stereochemistry Clinical Biochemistry Pharmaceutical Science Syk Crystal structure Crystallography X-Ray Biochemistry Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Humans Molecular Biology Protein Kinase Inhibitors Chemistry Kinase Organic Chemistry Protein-Tyrosine Kinases Combinatorial chemistry Drug Design Molecular Medicine Pyrazoles Selectivity Tyrosine kinase medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(9) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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