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Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK) |
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| Authors: | Colin H. MacKinnon Kevin Lau Jason D. Burch Yuan Chen Jonathon Dines Xiao Ding Charles Eigenbrot Alexander Heifetz Allan Jaochico Adam Johnson Joachim Kraemer Susanne Kruger Thomas M. Krülle Marya Liimatta Justin Ly Rosemary Maghames Christian A.G.N. Montalbetti Daniel F. Ortwine Zhonghua Pei |
| Affiliation: | 1. Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, United Kingdom;2. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States;3. Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany |
| Abstract: | 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. |
| Keywords: | ITK inhibitor TCR signalling Benzothiazole Anti-inflammatory Asthma SAR |
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