AZD4320, a dual inhibitor of bcl-2 and bcl-xl, induces tumor regression in hematologic cancer models without dose-limiting thrombocytopenia

Srividya B. Balachander, Steven W. Criscione, Kate F. Byth, Justin Cidado, Ammar Adam, Paula Lewis, Terry Macintyre, Shenghua Wen, Deborah Lawson, Kathleen Burke, Tristan Lubinski, Jeffrey W. Tyner, Stephen E. Kurtz, Shannon K. McWeeney, Jeffrey Varnes, R. Bruce Diebold, Thomas Gero, Stephanos Ioannidis, Edward J. Hennessy, William McCoullJamal C. Saeh, Areya Tabatabai, Omid Tavana, Nancy Su, Alwin Schuller, Mathew J. Garnett, Patricia Jaaks, Elizabeth A. Coker, Gareth P. Gregory, Andrea Newbold, Ricky W. Johnstone, Eric Gangl, Martin Wild, Michael Zinda, J. Paul Secrist, Barry R. Davies, Stephen E. Fawell, Francis D. Gibbons

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

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 clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL-mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL 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-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2- and Bcl-xL-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-xL-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-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.

Original languageEnglish
Pages (from-to)6535-6549
Number of pages15
JournalClinical Cancer Research
Volume26
Issue number24
DOIs
Publication statusPublished - Dec 2020

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