Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK)

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• 作者：Colin H. MacKinnon ; Kevin Lau ; Jason D. Burch ; Yuan Chen ; Jonathon Dines ; Xiao Ding ; Charles Eigenbrot ; Alex ; er Heifetz ; Allan Jaochico ; Adam Johnson ; Joachim Kraemer ; Susanne Kruger ; Thomas M. Kr眉lle ; Marya Liimatta ; Justin Ly ; Rosemary Maghames ; Christian A.G.N. Montalbetti ; Daniel F. Ortwine ; Yol ; a P茅rez-Fuertes ; Steven Shia ; et al.
• 关键词：ITK inhibitor ; TCR signalling ; Benzothiazole ; Anti-inflammatory ; Asthma ; SAR
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 December, 2013
• 年：2013
• 卷：23
• 期：23
• 页码：6331-6335
• 全文大小：2171 K

文摘

Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.