Related Experiment Video
Updated: Jan 6, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis
Mark F van Delft1,2, Stephane Chappaz3,4,5, Yelena Khakham3,4
1Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. vandelft@wehi.edu.au.
Abstract:
Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.
Insights
Blocking early apoptosis with WEHI-9625 preserves cell function. This novel small molecule targets VDAC2, inhibiting BAK-driven cell death before mitochondrial damage, offering a new therapeutic strategy.
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.
More Related Videos
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
01:17The Extrinsic Apoptotic Pathway