| Autor: |
Francis D. Gibbons, Stephen E. Fawell, Barry R. Davies, J. Paul Secrist, Michael Zinda, Martin Wild, Eric Gangl, Ricky W. Johnstone, Andrea Newbold, Gareth P. Gregory, Elizabeth A. Coker, Patricia Jaaks, Mathew J. Garnett, Alwin Schuller, Nancy Su, Omid Tavana, Areya Tabatabai, Jamal C. Saeh, William McCoull, Edward J. Hennessy, Stephanos Ioannidis, Thomas Gero, R. Bruce Diebold, Jeffrey Varnes, Shannon K. McWeeney, Stephen E. Kurtz, Jeffrey W. Tyner, Tristan Lubinski, Kathleen Burke, Deborah Lawson, Shenghua Wen, Terry Macintyre, Paula Lewis, Ammar Adam, Justin Cidado, Kate F. Byth, Steven W. Criscione, Srividya B. Balachander |
| Rok vydání: |
2023 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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