Abnormal and damaged proteins contribute to many diseases, from Alzheimer’s to cancer. Traditional drugs therefore target and deactivate one specific protein at a time. This works well when a disease is caused by a single type of protein, but complex diseases have many biological actors.
In a recent study published in Science, researchers affiliated with the Department of Molecular & Cell Biology and the Molecular Therapeutics Initiative activated enzymes that promote the removal of multiple harmful proteins. They tested the approach in cellular models of mitochondrial disorders, including COX deficiency syndrome and Friedreich’s ataxia. Enhancing the cells’ protein quality-control machinery improved mitochondrial function and protected neurons in these disease models.
“Quality control enzymes can protect you from hundreds of misfolded proteins,” said Michael Rapé, a professor of molecular therapeutics. “These are protective pathways that allow cells to survive all sorts of damage.”
The researchers hope the approach, called stimulated protein degradation, will eventually provide new ways to treat complex diseases.
The new strategy expands upon targeted protein degradation, an approach that uses small molecules to activate the cell’s degradation machinery, which uses a molecular tag called ubiquitin to mark specific proteins for destruction. The cell’s trash compactors break the marked proteins into amino acids, thus eliminating the biological threat.
Typical drug molecules bind themselves to problematic proteins and deactivate them, but because the protein isn’t destroyed, those molecules must stay attached. Targeted protein degradation reuses its molecules after destroying the targeted proteins, potentially making the strategy more adaptable and effective.
Targeted protein degradation generally directs a molecule toward a particular protein. That can be powerful when a disease has a well-defined target, but complex disorders often involve broader cellular dysfunction. Stimulated protein degradation takes a different route: activating protective pathways that can act on multiple proteins.
“An alternative to targeted protein degradation is to tap into those native protective functions that protect cell survival, turn them on, and make them more efficient,” said Rapé. “You stimulate the native protective function of these enzymes by degrading multiple proteins, and that allows you to take everything we learned from targeted protein degradation and move it towards complex diseases, neurodegeneration, and mitochondrial diseases.”
Rapé’s laboratory previously identified an E3 ligase complex called CUL2FEM1B and the BEX proteins that inhibit it. The collaborators explored several screening approaches to find ways of modulating that interaction. At the Drug Discovery Center, now part of the Molecular Therapeutics Initiative, Julia Schaletzky contributed to the design and analysis of a differential screening strategy that tested more than 120,000 compounds. In an independent follow-up analysis, she compared results from two binding assays and identified an unusual outlier: a compound that displaced BEX while preserving CUL2FEM1B’s recognition of its substrate. That unexpected result provided the chemical starting point for the mechanistic and disease-model studies that followed.
“We found a single outlier when I compared the results of two different screening assays,” said Schaletzky, the Molecular Therapeutics Initiative’s executive director. “What made it interesting was that it behaved differently from all the other compounds. Recognizing that difference opened up an entirely new direction for the project.”
Rapé noted that other E3 ligase complexes that handle cellular stress response mechanisms are regulated similarly to CUL2FEM1B, leading him to believe that similar approaches could offer additional therapeutic pathways. Some of these complexes control cell fate by regulating transcription factors; others control neurodegeneration through protein folding in the brain.
“This compound is also a first-of-a-kind activator of mitochondria,” said Rapé. “This opens up so many fields of research. That’s only possible if you try out really different avenues.”
The discovery reflects a longer effort to build translational drug discovery at UC Berkeley. When Schaletzky joined the university from the biotechnology industry in 2017, she suggested the establishment of a Drug Discovery Center. With support from professors Robert Tjian, Randy Schekman, Jeffery Cox, and then-dean Michael Botchan, as well as early philanthropic backing, she founded the center within the Henry Wheeler Center for Emerging and Neglected Diseases. The goal was to bring drug discovery expertise directly into UC Berkeley’s fundamental research environment, allowing promising discoveries to be explored as potential therapeutics, research tools, or new ventures.
In 2023, the Department of Molecular & Cell Biology created a Division of Molecular Therapeutics to train students on the entire drug discovery process. The following year, the Drug Discovery Center joined the new Molecular Therapeutics Initiative, led by Dan Nomura and Roberto Zoncu, expanding these capabilities through medicinal chemistry, preclinical development, and deeper integration with campus research.
“The Molecular Therapeutics Initiative is built in a way that allows you to tap very early into the amazing basic science that happens at Berkeley and test ideas rapidly,” said Rapé.
The Molecular Therapeutics Initiative was founded with a $10 million donation that funded shared infrastructure, including a chemical library and high-throughput screening tools. The combination of academic and industry expertise, supported by automation and flexible resources, makes it possible to explore high-risk ideas and pursue unexpected findings that might otherwise be missed. The stimulated protein degradation project drew on both the biological insight of the Rapé group and the exploratory drug discovery and analytical expertise of the Schaletzky group.
“We found one compound that behaved differently from the rest,” said Schaletzky. “Understanding why required the deep biological expertise of the Rapé Lab. Together, we uncovered a fundamentally new mechanism. That’s what makes the combination of basic research and exploratory drug discovery so powerful.”
Schaletzky observed that philanthropic investments fill a critical gap in biomedical research. Government agencies often focus on fundamental research that seeks to understand biological mechanisms, whereas translational funders often look for treatments that are ready for clinical trials and development. The Molecular Therapeutics Initiative frequently operates between the two areas at the preclinical development stage.
Rapé and Schaletzky are exploring the use of stimulated protein degradation in other contexts, such as Parkinson’s, heart failure, and aging-related diseases, which all have forms that involve mitochondrial dysfunction.
“We hope that this compound helps those patients as well,” said Rapé. “It really is a wonderful example of why the Molecular Therapeutics Initiative exists and how it can work.”
