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Preferential targeting of MCL-1 by a hydrocarbon-stapled BIM BH3 peptide
Abbas Hadji1, Greta K Schmitt1, Mathew R Schnorenberg1,2
1Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation and Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
Abstract:
BCL-2 family proteins are central regulators of apoptosis and represent prime therapeutic targets for overcoming cell death resistance in malignancies. However, plasticity of anti-apoptotic members, such as MCL-1, often allows for a switch in cell death dependency patterns that lie outside the binding profile of targeted BH3-mimetics. Therefore discovery of therapeutics that effectively inactivate all anti-apoptotic members is a high priority. To address this we tested the potency of a hydrocarbon stapled BIM BH3 peptide (BIM SAHB ) to overcome both BCL-2 and MCL-1 apoptotic resistance given BIM's naturally wide ranging affinity for all BCL-2 family multidomain members. BIM SAHB effectively killed diffuse large B-cell lymphoma (DLBCL) cell lines regardless of their anti-apoptotic dependence. Despite BIM BH3's ability to bind all BCL-2 anti-apoptotic proteins, BIM SAHB 's dominant intracellular target was MCL-1 and this specificity was exploited in sequenced combination BH3-mimetic treatments targeting BCL-2, BCL-XL, and BCL-W. Extending this MCL-1 functional dependence, mouse embryonic fibroblasts (MEFs) deficient in MCL-1 were resistant to mitochondrial changes induced by BIM SAHB . This study demonstrates the importance of understanding BH3 mimetic functional intracellular affinities for optimized use and highlights the diagnostic and therapeutic promise of a BIM BH3 peptide mimetic as a potential MCL-1 inhibitor.
Insights
A novel BIM BH3 peptide mimetic effectively targets MCL-1, overcoming resistance to apoptosis in cancer cells. This discovery offers a promising therapeutic strategy for malignancies by inhibiting anti-apoptotic proteins.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The BCL-2 protein family regulates apoptosis, making them key therapeutic targets in cancer.
- Resistance to apoptosis, particularly due to MCL-1 plasticity, poses a challenge for existing BH3-mimetic drugs.
- Developing therapeutics that inactivate all anti-apoptotic members is crucial for cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of a hydrocarbon stapled BIM BH3 peptide (BIM SAHB) against BCL-2 and MCL-1 mediated apoptosis resistance.
- To investigate the binding profile and dominant intracellular targets of BIM SAHB.
- To explore the therapeutic potential of BIM SAHB in combination treatments.
Main Methods:
- Testing BIM SAHB potency in diffuse large B-cell lymphoma (DLBCL) cell lines with varying anti-apoptotic dependencies.
- Assessing BIM SAHB's dominant intracellular target.
- Evaluating BIM SAHB efficacy in MCL-1 deficient mouse embryonic fibroblasts (MEFs).
- Utilizing sequenced combination BH3-mimetic treatments targeting BCL-2, BCL-XL, and BCL-W.
Main Results:
- BIM SAHB demonstrated efficacy in DLBCL cell lines irrespective of their anti-apoptotic protein dependence.
- The dominant intracellular target of BIM SAHB was identified as MCL-1.
- MCL-1 deficient MEFs exhibited resistance to BIM SAHB-induced mitochondrial changes.
- Combination therapies involving BIM SAHB showed promise.
Conclusions:
- Understanding the functional intracellular affinities of BH3 mimetics is vital for optimizing their use.
- BIM SAHB shows significant promise as a potential MCL-1 inhibitor for cancer therapy.
- This study highlights the diagnostic and therapeutic potential of BIM BH3 peptide mimetics.
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