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

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.

SUBMITTER: Tao ZF 

PROVIDER: S-EPMC4190639 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature