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Merck
  • 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 medicinal chemistry letters (2014-10-15)
Zhi-Fu Tao, Lisa Hasvold, Le Wang, Xilu Wang, Andrew M Petros, Chang H Park, Erwin R Boghaert, Nathaniel D Catron, Jun Chen, Peter M Colman, Peter E Czabotar, Kurt Deshayes, Wayne J Fairbrother, John A Flygare, Sarah G Hymowitz, Sha Jin, Russell A Judge, Michael F T Koehler, Peter J Kovar, Guillaume Lessene, Michael J Mitten, Chudi O Ndubaku, Paul Nimmer, Hans E Purkey, Anatol Oleksijew, Darren C Phillips, Brad E Sleebs, Brian J Smith, Morey L Smith, Stephen K Tahir, Keith G Watson, Yu Xiao, John Xue, Haichao Zhang, Kerry Zobel, Saul H Rosenberg, Chris Tse, Joel D Leverson, Steven W Elmore, Andrew J Souers
PMID25313317
摘要

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.