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Pharmacological Targeting of Executioner Proteins: Controlling Life and Death
Justin P Pogmore1,2, David Uehling3, David W Andrews1,2
1Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1J7, Canada.
Abstract:
Small-molecule mediated modulation of protein interactions of Bcl-2 (B-cell lymphoma-2) family proteins was clinically validated in 2015 when Venetoclax, a selective inhibitor of the antiapoptotic protein BCL-2, achieved breakthrough status designation by the FDA for treatment of lymphoid malignancies. Since then, substantial progress has been made in identifying inhibitors of other interactions of antiapoptosis proteins. However, targeting their pro-apoptotic counterparts, the "executioners" BAX, BAK, and BOK that both initiate and commit the cell to dying, has lagged behind. However, recent publications demonstrate that these proteins can be positively or negatively regulated using small molecule tool compounds. The results obtained with these molecules suggest that pharmaceutical regulation of apoptosis will have broad implications that extend beyond activating cell death in cancer. We review recent advances in identifying compounds and their utility in the exogenous control of life and death by regulating executioner proteins, with emphasis on the prototype BAX.
Insights
Targeting BCL-2 family proteins with small molecules is advancing. Recent research shows promise in modulating pro-apoptotic proteins like BAX, BAK, and BOK, expanding therapeutic potential beyond cancer.
Area of Science:
- Molecular Biology
- Pharmacology
- Biochemistry
Background:
- Small-molecule inhibitors targeting anti-apoptotic BCL-2 family proteins, like Venetoclax, have shown clinical success in lymphoid malignancies.
- Research has focused on inhibiting anti-apoptotic proteins, but targeting pro-apoptotic 'executioner' proteins (BAX, BAK, BOK) has lagged.
Purpose of the Study:
- To review recent advances in identifying small molecule compounds that modulate the function of pro-apoptotic BCL-2 family proteins.
- To discuss the utility of these compounds in controlling cell death pathways, with a focus on BAX.
Main Methods:
- Literature review of recent publications on small molecule modulators of BCL-2 family proteins.
- Analysis of studies demonstrating the use of tool compounds to regulate BAX, BAK, and BOK activity.
Main Results:
- Recent publications show that pro-apoptotic proteins BAX, BAK, and BOK can be regulated by small molecule tool compounds.
- These compounds offer potential for both positive and negative modulation of apoptosis initiation and commitment.
Conclusions:
- Pharmaceutical regulation of apoptosis through targeting executioner proteins has broad implications beyond cancer therapy.
- Advances in small molecule modulators of BAX and related proteins represent a significant step in controlling cell life and death pathways.
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