Bcl-2 family proteins are key regulators of apoptosis and thus attractive targets for cancer therapy. The overexpression of Bcl-xL is well correlated with drug resistance and disease progression of multiple solid tumors and hematologic malignancies. The dual Bcl-xL/Bcl-2 inhibitor navitoclax is currently in clinical development; however a small molecule that is potent against and selective for Bcl-xL has not yet been reported. In order to explore the effects of selective Bcl-xL inhibition, based on a HTS hit, we used structure-based-design and NMR-based fragment screening to generate small molecule 1 . This compound binds to Bcl-xL with low picomolar affinity and shows vast selectivity over related Bcl-2 protein family members. Compound 1 causes mechanism dependent apoptosis in tumor cell lines that depend upon Bcl-xL for survival, as well as strong synergy with chemotherapies in vitro. Additionally, dosing in immunocompromised mice xenografted with cells derived from a small cell lung cancer line afforded tumor growth inhibition as a single agent. A rapid decrease in platelets driven by Bcl-xL inhibition was observed, with recovery at 72 hours as consistent with the platelet recovery kinetics of navitoclax. This is the first in vivo characterization of a truly selective Bcl-xL inhibitor. Compound 1 thus represents an excellent tool for studying Bcl-2 family biology as well as basis for further development of Bcl-xLselective inhibitors for the treatment of cancer. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/242nm/uploads/87954_figure_1.jpg' alt='' />

Discovery of a highly potent and in vivo efficacious Bcl-xL selective inhibitor

245th National Meeting (2013)

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