Azd4320, A Dual Inhibitor Of Bcl-2 And Bcl-X(L), Induces Tumor Regression In Hematologic Cancer Models Without Dose-Limiting Thrombocytopenia

Purpose 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 dinic, another family member, Bcl-x(L), has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-x(L) inhibitor that broadens the therapeutic activity while minimizing Bcl-x(L)-mediated thrombocytopenia.Experimental Design: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-x(L) and assessed the activity against in vitro cell lines, patient samples, and in vivo 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.Results: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-x(L), and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2- and Bcl-x(L)-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(L)-dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.Conclusions: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-x(L) inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.