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Updated: May 24, 2025

Examining BCL-2 Family Function with Large Unilamellar Vesicles
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Differential regulation of BAX and BAK apoptotic activity revealed by small molecules

Kaiming Li1,2, Yu Q Yap1,2, Donia M Moujalled1,2

  • 1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Science Advances
|March 5, 2025
PubMed

Insights

A novel molecule, WEHI-3773, modulates apoptosis by targeting the interaction between VDAC2 and pro-apoptotic proteins BAK and BAX. This drug promotes cell death in certain leukemias, offering a new therapeutic avenue.

Area of Science:

  • Cellular biology
  • Molecular medicine
  • Biochemistry

Background:

  • Defective apoptosis involving B cell lymphoma 2 antagonist/killer (BAK) and B cell lymphoma 2-associated X protein (BAX) contributes to various diseases.
  • Voltage-dependent anion channel 2 (VDAC2) regulates BAK and BAX activity at the mitochondria.

Purpose of the Study:

  • To identify and characterize a small molecule that modulates VDAC2 interactions with BAK and BAX.
  • To investigate the therapeutic potential of this molecule in overcoming resistance to apoptosis inhibitors.

Main Methods:

  • Small molecule screening to identify VDAC2-BAK/BAX interaction inhibitors.
  • Cell-based assays to assess apoptosis induction.
  • Mitochondrial recruitment assays for BAK and BAX.
  • Evaluation of drug resistance models in leukemia.

Main Results:

  • WEHI-3773 inhibits VDAC2-BAX interaction, reducing BAX-mediated apoptosis.
  • WEHI-3773 promotes BAK-mediated apoptosis by disrupting VDAC2-BAK sequestration.
  • The molecule induces apoptosis in cells co-expressing BAK and BAX, driven by BAK.
  • WEHI-3773 overcomes venetoclax resistance in BAX-deficient leukemias by enhancing BAK activity.

Conclusions:

  • VDAC2 plays a critical role in coordinating BAK and BAX apoptotic functions.
  • WEHI-3773 differentially regulates BAK and BAX, promoting apoptosis through a BAK-dependent feed-forward loop.
  • Targeting the VDAC2-BAK/BAX interaction with WEHI-3773 presents a promising strategy for treating pathologies associated with defective apoptosis and drug resistance.

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