A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis.

Area of Science:

• Cellular Biology
• Molecular Biology
• Pharmacology

Background:

• Activating apoptosis is a validated cancer therapy.
• Blocking apoptosis to protect healthy cells has been challenging.
• Caspase inhibitors act late, limiting their protective effect.

Purpose of the Study:

• To investigate a novel approach for blocking apoptosis before mitochondrial damage.
• To evaluate the efficacy of WEHI-9625 in preventing cell death.
• To explore the role of VDAC2 in regulating apoptosis.

Main Methods:

• Utilized a novel tricyclic sulfone small molecule, WEHI-9625.
• Assessed WEHI-9625's binding to VDAC2.
• Determined the effect of WEHI-9625 on BAK-mediated apoptosis.
• Evaluated cellular function and clonogenic potential post-treatment.

Main Results:

• WEHI-9625 binds to VDAC2, enhancing its apoptosis-inhibitory function.
• The molecule inhibits apoptosis driven by mouse BAK.
• WEHI-9625 blocks apoptosis prior to mitochondrial damage.
• Cellular function and long-term clonogenic potential were preserved.

Conclusions:

• Blocking apoptosis at an early stage, before mitochondrial damage, is advantageous.
• WEHI-9625 represents a pharmacologically tractable method for early apoptosis inhibition.
• VDAC2 plays a critical role in regulating apoptosis, offering a therapeutic target.