High-Throughput Screening and Hit Validation of Extracellular-Related Kinase 5 (ERK5) Inhibitors

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• 作者：Stephanie M. Myers ; Ruth H. Bawn ; Louise C. Bisset ; Timothy J. Blackburn ; Betty Cottyn ; Lauren Molyneux ; Ai-Ching Wong ; Celine Cano ; William Clegg ; Ross. W. Harrington ; Hing Leung ; Laurent Rigoreau ; Sandrine Vidot ; Bernard T. Golding ; Roger J. Griffin ; Tim Hammonds ; David R. Newell ; Ian R. Hardcastle
• 刊名：ACS Combinatorial Science
• 出版年：2016
• 出版时间：August 8, 2016
• 年：2016
• 卷：18
• 期：8
• 页码：444-455
• 全文大小：656K
• 年卷期：0
• ISSN：2156-8944

文摘

The extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP progressive binding system, and used to identify hits from a library of 57 617 compounds. Four distinct chemical series were evident within the screening hits. Resynthesis and reassay of the hits demonstrated that one series did not return active compounds, whereas three series returned active hits. Structure–activity studies demonstrated that the 4-benzoylpyrrole-2-carboxamide pharmacophore had excellent potential for further development. The minimum kinase binding pharmacophore was identified, and key examples demonstrated good selectivity for ERK5 over p38α kinase.