Scientists Discover Irreversible Peptide Inhibitors for Previously ‘Undruggable’ Cancer Targets
For the first time, researchers have successfully identified drug candidates capable of binding irreversibly to a cancer-related protein that was previously considered “undruggable.” These inhibitors permanently block the protein’s function, offering a new therapeutic approach.
Transcription factors, which act as master regulators of gene expression, play a significant role in cancer progression. Traditional drug development efforts using small molecules to target these proteins have largely failed. As a result, scientists have turned to peptides—short chains of amino acids—to develop effective inhibitors.
Now, a research team from the University of Bath has demonstrated a novel strategy to discover peptides that selectively and irreversibly bind within cells, effectively neutralizing the cancer-driving transcription factor cJun. Their findings, published in Advanced Science, highlight a breakthrough in cancer drug discovery.
A New Screening Platform for Drug Discovery
The researchers employed an innovative screening technology known as the Transcription Block Survival (TBS) assay, which enables the rapid testing of numerous peptides to identify those that can “switch off” oncogenic transcription factors.
Their previous research led to the identification of reversible inhibitors of cJun. However, this latest study marks a significant advancement by uncovering peptides that permanently block the transcription factor’s activity within cells.
cJun is a protein composed of two identical subunits that bind to DNA and regulate gene expression. When overactive, it drives excessive cell growth, contributing to cancer progression. The researchers designed a peptide inhibitor that binds to one half of the cJun protein, preventing it from pairing and interacting with DNA.
After successfully developing a peptide that could bind to cJun, they modified it to ensure an irreversible attachment, effectively rendering the protein inactive.
A Powerful ‘Harpoon’ Against Cancer
The inhibitor functions like a molecular harpoon, latching onto cJun and preventing it from binding to DNA. Unlike previous reversible inhibitors, this approach ensures a long-lasting effect, making it a promising therapeutic candidate.
“This is the first time we’ve managed to block a transcription factor irreversibly using a peptide inhibitor,” said Dr. Andy Brennan, the study’s first author and a research fellow at the University of Bath’s Department of Life Sciences.
To validate their findings, the researchers incorporated cJun binding sites into an essential gene in lab-grown cells. Normally, cJun would bind to these sites, deactivating the gene and causing cell death. However, when blocked by the peptide inhibitor, the gene remained active, allowing the cells to survive.
Overcoming Drug Development Challenges
Professor Jody Mason, Chief Scientific Officer of Revolver Therapeutics and a biochemistry professor at the University of Bath, emphasized the advantages of this approach.
“Many drug candidates that show promise in lab tests fail due to toxicity or poor cell penetration. However, our screening platform evaluates peptide activity directly within living cells, addressing these common challenges.”
This method ensures that the inhibitors remain effective in a complex cellular environment, where various proteins and enzymes might otherwise degrade or interfere with their function. It also allows for real-time toxicity assessments.
The researchers believe their technology could lead to the discovery of additional promising drug candidates for other hard-to-target cancer proteins.
