Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton鈥檚 Tyrosine Kinase

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• 作者：Christopher R. Smith ; Douglas R. Dougan ; Mallareddy Komandla ; Toufike Kanouni ; Beverly Knight ; J. David Lawson ; Mark Sabat ; Ewan R. Taylor ; Phong Vu ; Corey Wyrick
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5437-5444
• 全文大小：417K
• ISSN：1520-4804

文摘

The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton鈥檚 tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.