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

A-1155463 is a highly potent and selective BCL-XL inhibitor identified through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound exhibits significantly greater potency against BCL-XL-dependent cell lines compared to our previously reported inhibitor, WEHI-539, while avoiding its pharmaceutical liabilities. In mouse studies, A-1155463 induced a mechanism-based and reversible thrombocytopenia and effectively inhibited the growth of H146 small cell lung cancer xenograft tumors after multiple doses. Consequently, A-1155463 serves as an excellent tool for investigating BCL-XL biology and as a promising lead for further optimization.