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Discovery of a potent and selective BCL-XL inhibitor with in vivo activity


Tao, ZF; Hasvold, L; Wang, L; Wang, X; Petros, AM; Park, CH; Boghaert, ER; Catron, ND; Chen, J; Colman, PM; Czabotar, PE; Deshayes, K; Fairbrother, WJ; Flygare, JA; Hymowitz, SG; Jin, S; Judge, RA; Koehler, MF; Kovar, PJ; Lessene, G; Mitten, MJ; Ndubaku, CO; Nimmer, P; Purkey, HE; Oleksijew, A; Phillips, DC; Sleebs, BE; Smith, BJ; Smith, ML; Tahir, SK; Watson, KG; Xiao, Y; Xue, J; Zhang, H; Zobel, K; Rosenberg, SH; Tse, C; Leverson, JD; Elmore, SW; Souers, AJ
2014-08-26
ACS Med Chem Lett
Journal Article
5
10
1088-93
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.
ACS
Structural Biology; Chemical Biology
10.1021/ml5001867
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2014-10-16 03:19:24 Last Modified 2015-03-24 09:55:31