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AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-xL, Induces Tumor Regression in Hematologic Cancer Models without
Srividya B Balachander1, Steven W Criscione1, Kate F Byth1
1Bioscience, Oncology R&D, AstraZeneca, Boston, Massachusetts.
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.
Insights
A new dual inhibitor, AZD4320, targets Bcl-2 and Bcl-xL proteins crucial in many cancers. It shows promise in treating hematologic cancers, including acute myeloid leukemia, with manageable side effects like transient thrombocytopenia.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bcl-2 family proteins are key regulators of apoptosis and are frequently dysregulated in cancer.
- Selective inhibitors like venetoclax targeting Bcl-2 have shown clinical success, but resistance mechanisms involving Bcl-xL necessitate broader targeting strategies.
- Bcl-xL inhibition is a potential therapeutic avenue, but often associated with dose-limiting thrombocytopenia.
Purpose of the Study:
- To develop and characterize a novel dual inhibitor targeting both Bcl-2 and Bcl-xL.
- To evaluate the efficacy and safety profile of this dual inhibitor in preclinical cancer models.
- To explore its potential to overcome resistance mechanisms and minimize Bcl-xL-mediated side effects.
Main Methods:
- Structure-based drug design was employed to create a small-molecule dual Bcl-2/Bcl-xL inhibitor.
- In vitro assays using cancer cell lines and patient samples assessed anti-cancer activity.
- In vivo studies in animal models and pharmacokinetic/pharmacodynamic (PK/PD) modeling were used to evaluate efficacy and safety.
- Comparison with a Bcl-2 selective inhibitor (venetoclax) was performed.
Main Results:
- AZD4320 demonstrated nanomolar affinity for both Bcl-2 and Bcl-xL, inducing cancer cell death via the mitochondrial apoptotic pathway.
- The drug showed significant activity in Bcl-2 and Bcl-xL dependent hematologic cancer cell lines and enhanced efficacy in acute myeloid leukemia (AML) patient samples compared to venetoclax.
- A single dose of AZD4320 led to tumor regression with transient thrombocytopenia that recovered within a week, suggesting potential for weekly dosing.
- AZD4320 exhibited monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.
Conclusions:
- AZD4320 is a potent dual Bcl-2/Bcl-xL inhibitor with a manageable thrombocytopenia risk profile.
- This molecule offers a promising strategy for treating a wide range of cancers with Bcl-2 family protein dysregulation.
- Further clinical exploration of AZD4320 is warranted for its broad therapeutic potential in various tumor types.
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