Discovery of a Potent and Selective BCL-X <sub>L</sub> Inhibitor with <i>in Vivo</i> Activity
Zhi‐Fu Tao(AbbVie (United States)), Lisa Hasvold(AbbVie (United States)), Le Wang(AbbVie (United States)), Xilu Wang(AbbVie (United States)), Andrew M. Petros(AbbVie (United States)), Chang H. Park(AbbVie (United States)), Erwin R. Boghaert(AbbVie (United States)), Nathaniel D. Catron(AbbVie (United States)), Jun Chen(AbbVie (United States)), Peter M. Colman(The University of Melbourne), Peter E. Czabotar(The University of Melbourne), Kurt Deshayes, Wayne J. Fairbrother, John A. Flygare, S.G. Hymowitz, Sha Jin(AbbVie (United States)), Russell A. Judge(AbbVie (United States)), Michael F. T. Koehler, Peter Kovar(AbbVie (United States)), Guillaume Lessène(The University of Melbourne), Michael J. Mitten(AbbVie (United States)), Chudi Ndubaku, Paul Nimmer(AbbVie (United States)), Hans E. Purkey, Anatol Oleksijew(AbbVie (United States)), Darren C. Phillips(AbbVie (United States)), Brad E. Sleebs(The University of Melbourne), Brian J. Smith(The University of Melbourne), Morey L. Smith(AbbVie (United States)), Stephen K. Tahir(AbbVie (United States)), Keith G. Watson(The University of Melbourne), Xiao Yu(AbbVie (United States)), John Xue(AbbVie (United States)), Haichao Zhang(AbbVie (United States)), Kerry Zobel, Saul H. Rosenberg(AbbVie (United States)), Chris Tse(AbbVie (United States)), Joel D. Leverson(AbbVie (United States)), Steven W. Elmore(AbbVie (United States)), Andrew J. Souers(AbbVie (United States))
Cited by 330Open Access
Abstract
A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-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-XL biology as well as a productive lead structure for further optimization.
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