A team of scientists in Australia has discovered a small molecule that selectively blocks a key protein involved in cell death, a finding that could lead to the development of treatments for neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease (AD). The study, led by researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) and published in Science Advances, identifies a compound named WEHI-3773 that interferes with the interaction between the apoptosis effector proteins BAX and BAK and their regulator, VDAC2, in mitochondria.
“Currently, there are no treatments that prevent neurons from dying to slow the progression of Parkinson’s. Any drugs that could be able to do this could be game-changing,” said one of the study’s corresponding authors, Grant Dewson, PhD, professor and head of the WEHI Parkinson’s Disease Research Centre.
Using high-throughput screening of more than 100,000 compounds at the National Drug Discovery Centre, the research team identified WEHI-3773 as a molecule capable of disrupting the BAX:VDAC2 interaction, which prevented BAX from inducing cell death. “We were thrilled to find a small molecule that targets a killer protein called BAX and stops it working,” said co-corresponding author Guillaume Lessene, PhD, head of new medicines and diagnostics at WEHI. “While not the case in most cells, in neurons, turning off BAX alone may be sufficient to limit cell death.”
The research builds on decades of apoptosis studies at WEHI, including the 1988 discovery of a protein that inhibits programmed cell death, which eventually contributed to the development of anti-cancer therapies. Unlike drugs that activate apoptosis to treat cancer, this study takes a different approach by blocking apoptosis where excessive cell death is pathological, as in neurodegeneration.
The compound WEHI-3773 functions by inhibiting BAX’s recruitment to mitochondria via VDAC2, effectively keeping BAX in the cytosol and away from its site of action. “For the first time, we could keep BAX away from mitochondria and keep cells alive using this molecule,” said lead author Kaiming Li, a PhD candidate at WEHI working in the Dewson lab. “This could pave the way for next-generation cell death inhibitors to combat degenerative conditions.”
The study showed that WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated apoptosis by limiting inhibitory sequestration by VDAC2.”
This dual action of WEHI-3773 that suppresses BAX while enhancing BAK activity is relevant in neurons, where BAX is often retained but BAK is downregulated, allowing targeted inhibition of apoptosis in brain cells.
The potential implications for the development of next-generation treatments for neurodegenerative diseases are significant. Neurons affected in Parkinson’s disease and AD undergo premature death, yet existing therapies only address symptoms without halting disease progression. By targeting mitochondrial cell death mechanisms, WEHI-3773 represents a new strategy for developing disease-modifying therapies.
Additionally, the researchers noted that the compound also has potential for the treatment of cancer. Resistance to the drug venetoclax, a BCL-2 inhibitor used in leukemia, is sometimes driven by loss of BAX function. WEHI-3773 was found to overcome this resistance by enhancing BAK-dependent apoptosis, which suggests it could be used to enhance the response to existing cancer therapies.
While WEHI-3773’s effects were consistent in cell lines when combined with BH3 mimetics, its behavior under different apoptotic stimuli was variable, the researchers noted. In addition, the molecular structure of the VDAC2 binding sites for BAX and BAK remains undefined, but provides a fertile area for additional research.
Next steps for the WEHI team include mapping the molecular structure of the VDAC2 binding sites and testing WEHI-3773 and related compounds in animal models of neurodegeneration and cancer. The WEHI Parkinson’s Disease Research Centre plans to continue building upon its focus on cell death, mitochondrial biology, and inflammation to develop disease-modifying drugs aimed at transforming care for patients with progressive neurodegenerative conditions.
