Literature DB >> 25313317

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

Zhi-Fu Tao1, Lisa Hasvold1, Le Wang1, Xilu Wang1, Andrew M Petros1, Chang H Park1, Erwin R Boghaert1, Nathaniel D Catron1, Jun Chen1, Peter M Colman2, Peter E Czabotar2, Kurt Deshayes3, Wayne J Fairbrother3, John A Flygare3, Sarah G Hymowitz3, Sha Jin1, Russell A Judge1, Michael F T Koehler3, Peter J Kovar1, Guillaume Lessene4, Michael J Mitten1, Chudi O Ndubaku3, Paul Nimmer1, Hans E Purkey3, Anatol Oleksijew1, Darren C Phillips1, Brad E Sleebs2, Brian J Smith2, Morey L Smith1, Stephen K Tahir1, Keith G Watson2, Yu Xiao1, John Xue1, Haichao Zhang1, Kerry Zobel3, Saul H Rosenberg1, Chris Tse1, Joel D Leverson1, Steven W Elmore1, Andrew J Souers1.   

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.

Entities:  

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

Year:  2014        PMID： 25313317      PMCID： PMC4190639          DOI： 10.1021/ml5001867

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


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