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ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93. doi: 10.1021/ml5001867. eCollection 2014 Oct 9.

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

Author information

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.

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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