Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

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• 作者：Zhi-Fu Tao ; Lisa Hasvold ; Le Wang ; Xilu Wang ; Andrew M. Petros ; Chang H. Park ; Erwin R. Boghaert ; Nathaniel D. Catron ; Jun Chen ; Peter M. Colman ; Peter E. Czabotar ; Kurt Deshayes ; Wayne J. Fairbrother ; John A. Flygare ; Sarah G. Hymowitz ; Sha Jin ; Russell A. Judge ; Michael F. T. Koehler ; Peter J. Kovar ; Guillaume Lessene ; Michael J. Mitten ; Chudi O. Ndubaku ; Paul Nimmer ; Hans E. Purkey ; Anatol Oleksijew ; Darren C. Phillips ; Brad E. Sleebs ; Brian J. Smith ; Morey L. Smith ; Stephen K. Tahir ; Keith G. Watson ; Yu Xiao ; John Xue ; Haichao Zhang ; Kerry Zobel ; Saul H. Rosenberg ; Chris Tse ; Joel D. Leverson ; Steven W. Elmore ; Andrew J. Souers
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：5
• 期：10
• 页码：1088-1093
• 全文大小：367K
• ISSN：1948-5875

文摘

A-1155463, a highly potent and selective BCL-X_L inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-X_L-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-X_L biology as well as a productive lead structure for further optimization.

Keywords:

BCL-X_L; BCL-2; apoptosis; cancer