Discovery of a Potent and Selective BCL-X L Inhibitor with in Vivo Activity
ACS Medicinal Chemistry Letters2014Vol. 5(10), pp. 1088–1093
Citations Over TimeTop 10% of 2014 papers
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, S.G. Hymowitz, Sha Jin, Russell A. Judge, Michael F. T. Koehler, Peter Kovar, Guillaume Lessène, Michael J. Mitten, Chudi 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, Xiao Yu, John Xue, Haichao Zhang, Kerry Zobel, Saul H. Rosenberg, Chris Tse, Joel Johansson, Steven W. Elmore, Andrew J. Souers
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.
Related Papers
- → Comparison of an in vitro method and an in vivo method of Giardia excystation(1992)23 cited
- → IN VITRO SPECIFICITY AND IN VIVO ACTIVITY OF ANTIMACROPHAGE SERUM(1974)4 cited
- → Actin Organization as an in Vitro Assay for Tumorigenicity(1982)2 cited
- [Pharmacodynamic study of the in vitro clonogenic assay--with reference to dose levels].(1988)
- The release of the marked insulin J125 from ointment in vitro and in vivo.(1993)