2. Academic Validation
  3. Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

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

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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