TY - JOUR
T1 - AZD4320, a dual inhibitor of bcl-2 and bcl-xl, induces tumor regression in hematologic cancer models without dose-limiting thrombocytopenia
AU - Balachander, Srividya B.
AU - Criscione, Steven W.
AU - Byth, Kate F.
AU - Cidado, Justin
AU - Adam, Ammar
AU - Lewis, Paula
AU - Macintyre, Terry
AU - Wen, Shenghua
AU - Lawson, Deborah
AU - Burke, Kathleen
AU - Lubinski, Tristan
AU - Tyner, Jeffrey W.
AU - Kurtz, Stephen E.
AU - McWeeney, Shannon K.
AU - Varnes, Jeffrey
AU - Diebold, R. Bruce
AU - Gero, Thomas
AU - Ioannidis, Stephanos
AU - Hennessy, Edward J.
AU - McCoull, William
AU - Saeh, Jamal C.
AU - Tabatabai, Areya
AU - Tavana, Omid
AU - Su, Nancy
AU - Schuller, Alwin
AU - Garnett, Mathew J.
AU - Jaaks, Patricia
AU - Coker, Elizabeth A.
AU - Gregory, Gareth P.
AU - Newbold, Andrea
AU - Johnstone, Ricky W.
AU - Gangl, Eric
AU - Wild, Martin
AU - Zinda, Michael
AU - Secrist, J. Paul
AU - Davies, Barry R.
AU - Fawell, Stephen E.
AU - Gibbons, Francis D.
N1 - Funding Information:
We acknowledge the support of Prasad Nadella for reading IHC slides, Galina Repik and Cheryl Campbell for generating data, Kelly Theriault for generating constructs, Meghan Scarpitti for retroviral support, Erin Code and Xiahui Zhu for preparing purified Bcl-2 family proteins for the FP assays, Clare Hoover for reading the platelet data, and Patrick Brassil for DMPK support. The Sanger panel screen was supported by the Wellcome Trust grant 206194 (to M.J. Garnett).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-20-0863
DO - 10.1158/1078-0432.CCR-20-0863
M3 - Article
C2 - 32988967
AN - SCOPUS:85099865354
SN - 1078-0432
VL - 26
SP - 6535
EP - 6549
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -