Data from AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-x_L, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia

Abstract

<div>AbstractPurpose:<p>Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had success in the clinic, another family member, Bcl-x<sub>L</sub>, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-x<sub>L</sub> inhibitor that broadens the therapeutic activity while minimizing Bcl-x<sub>L</sub>–mediated thrombocytopenia.</p>Experimental Design:<p>We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-x<sub>L</sub> and assessed the activity against <i>in vitro</i> cell lines, patient samples, and <i>in vivo</i> models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time.</p>Results:<p>We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-x<sub>L</sub>, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-x<sub>L</sub>–dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-x<sub>L</sub>–dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.</p>Conclusions:<p>AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-x<sub>L</sub> inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.</p></div>