X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase
In: Bioorganic & Medicinal Chemistry Letters, Jg. 22 (2012-05-01), Heft 9, S. 3296-3300
academicJournal
Zugriff:
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. [Copyright &y& Elsevier]
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X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase
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Autor/in / Beteiligte Person: | McLean, Larry R. ; Zhang, Ying ; Zaidi, Nisha ; Bi, Xiping ; Wang, Rachel ; Dharanipragada, Ram ; Jurcak, John G. ; Gillespy, Timothy A. ; Zhao, Zhicheng ; Musick, Kwon Y. ; Choi, Yong-Mi ; Barrague, Matthieu ; Peppard, Jane ; Smicker, Matthew ; Duguid, Mei ; Parkar, Ashfaq ; Fordham, Jeremy ; Kominos, Dorothea |
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Zeitschrift: | Bioorganic & Medicinal Chemistry Letters, Jg. 22 (2012-05-01), Heft 9, S. 3296-3300 |
Veröffentlichung: | 2012 |
Medientyp: | academicJournal |
ISSN: | 0960-894X (print) |
DOI: | 10.1016/j.bmcl.2012.03.016 |
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