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

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

doi:10.1021/ml5001867

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

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

Authors

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

Affiliations

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.