Journal article
Discovery of a potent and selective BCL-XLinhibitor with in vivo activity
ZF Tao, L Hasvold, L Wang, X Wang, AM Petros, CH Park, ER Boghaert, ND Catron, J Chen, PM Colman, PE Czabotar, K Deshayes, WJ Fairbrother, JA Flygare, SG Hymowitz, S Jin, RA Judge, MFT Koehler, PJ Kovar, G Lessene Show all
ACS Medicinal Chemistry Letters | Published : 2014
DOI: 10.1021/ml5001867
Abstract
A-1155463, a highly potent and selective BCL-XLinhibitor, 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-XLbiology as well as a productive lead structure for further optimization.
Grants
Awarded by Genentech
Funding Acknowledgements
This work was sponsored by AbbVie, Inc., and Genentech, a member of the Roche group. Part of this work was supported by fellowships and grants from the Australian Research Council (fellowship to P.E.C.), the National Health and Medical Research Council (NHMRC, fellowships to P.M.C.; development grant 305536 and program grants 257502, 461221, and 1016701), the Leukemia and Lymphoma Society (specialized center of research grant nos. 7015 and 7413), the Cancer Council of Victoria (fellowship to P.M.C.; grant-in-aid 461239), and the Australian Cancer Research Foundation. Infrastructure support from the NHMRC Independent Research Institutes Infrastructure Support Scheme grant no. 361646 and a Victorian State Government OIS grant are gratefully acknowledged.