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Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic
A W Roberts1,2,3,4, Dcs Huang2,3
1Integrated Department of Clinical Hematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Australia.
Abstract:
The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2.
Insights
B-cell-lymphoma-2 (BCL2) inhibitors, like Venetoclax, offer new hope for treating chronic lymphocytic leukemia (CLL) and other B-cell cancers by blocking cell survival mechanisms. Further research is exploring their full clinical potential.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The B-cell-lymphoma-2 (BCL2) protein promotes cell survival and is a key target in cancer therapy.
- Targeting protein-protein interactions, like BCL2's role in apoptosis, presented significant challenges.
- BH3-mimetics, small molecules inhibiting BCL2, emerged as a therapeutic strategy.
Purpose of the Study:
- To review the scientific basis for BCL2 inhibitors in cancer treatment.
- To explore the current clinical utility and unresolved questions regarding BCL2 inhibitors.
- To assess the application of BCL2 inhibitors in chronic lymphocytic leukemia (CLL) and other B-cell malignancies.
Main Methods:
- Review of scientific literature on BCL2 protein function and inhibition.
- Analysis of clinical data and approvals for BCL2 inhibitors, such as Venetoclax.
- Exploration of the mechanism of action of BH3-mimetics.
Main Results:
- Venetoclax is the first FDA-approved BCL2 inhibitor for specific chronic lymphocytic leukemia (CLL) cases.
- High-affinity BH3-mimetic molecules have been successfully developed.
- BCL2 is a validated therapeutic target in certain B-cell malignancies.
Conclusions:
- BCL2 inhibitors represent a significant advancement in cancer therapy, particularly for B-cell malignancies.
- Further investigation is needed to fully understand the clinical utility and optimize the use of BCL2 inhibitors.
- The development of BH3-mimetics has overcome previous challenges in targeting protein-protein interactions.
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