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

  • ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93. doi: 10.1021/ml5001867.
Zhi-Fu Tao  1 ,  Lisa Hasvold  1 ,  Le Wang  1 ,  Xilu Wang  1 ,  Andrew M Petros  1 ,  Chang H Park  1 ,  Erwin R Boghaert  1 ,  Nathaniel D Catron  1 ,  Jun Chen  1 ,  Peter M Colman  2 ,  Peter E Czabotar  2 ,  Kurt Deshayes  3 ,  Wayne J Fairbrother  3 ,  John A Flygare  3 ,  Sarah G Hymowitz  3 ,  Sha Jin  1 ,  Russell A Judge  1 ,  Michael F T Koehler  3 ,  Peter J Kovar  1 ,  Guillaume Lessene  4 ,  Michael J Mitten  1 ,  Chudi O Ndubaku  3 ,  Paul Nimmer  1 ,  Hans E Purkey  3 ,  Anatol Oleksijew  1 ,  Darren C Phillips  1 ,  Brad E Sleebs  2 ,  Brian J Smith  2 ,  Morey L Smith  1 ,  Stephen K Tahir  1 ,  Keith G Watson  2 ,  Yu Xiao  1 ,  John Xue  1 ,  Haichao Zhang  1 ,  Kerry Zobel  3 ,  Saul H Rosenberg  1 ,  Chris Tse  1 ,  Joel D Leverson  1 ,  Steven W Elmore  1 ,  Andrew J Souers  1
Affiliations
  • 1. AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
  • 2. The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia.
  • 3. Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
  • 4. The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia ; Department of Pharmacology and Therapeutics, The University of Melbourne , Parkville, VIC 3010, Australia.
PMID: 25313317 DOI: 10.1021/ml5001867
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.

Keywords
BCL-2; BCL-XL; apoptosis; cancer.
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