Protein鈥揕igand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase

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• 作者：Richard A. Norman ; Anne-Kathrin Schott ; David M. Andrews ; Jason Breed ; Kevin M. Foote ; Andrew P. Garner ; Derek Ogg ; Jonathon P. Orme ; Jennifer H. Pink ; Karen Roberts ; David A. Rudge ; Andrew P. Thomas ; Andrew G. Leach
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5003-5012
• 全文大小：480K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein鈥搇igand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.