Peptide breakthrough curbs ‘undruggable’ cancer switch
28 Mar 2025

Researchers have outlined a means to apply drug treatments to previously resistant protein which can play a key role in cancer development.
Transcription factor proteins act as switches for gene behaviour but have frustrated attempts to curb their activity in promoting cancers.
Now scientists based at the University of Bath report significant progress using peptide small protein fragments to block the behaviour of one transcription factor, cJun.
Its two identical halves are designed to bind either side of a DNA strand and enabled them to direct gene expression. This can become overactive in the case of cancer reported the research team, writing in Advanced Science.
Their solution was to create a peptide that itself binded to cJun then modify it to bind irreversibly to the transcription factor.
Bath department of life science research fellow Dr Andy Brennan was first author of the study said the work built on previous research to create an earlier inhibitor.
“We’d previously identified reversible inhibitors but this is the first time we’ve managed to block a transcription factor irreversibly with a peptide inhibitor,” explained Brennan.
“The [revised] inhibitor works a bit like a harpoon that fires across to the target and won’t let go – it grips the cJun tightly and stops it from binding to the DNA.
The work employed a new drug discovery screening platform, the Transcription Block Survival (TBS) assay, able to test a large number of peptides in order to effectively switch off transcription factors that impact cancer development.
Professor of biochemistry and CSO of Revolver Therapeutics Jody Mason explained: “Many drug candidates that are effective in vitro turn out to be toxic or don’t penetrate cancer cells at all.
“However, our platform screens for peptide activity directly in the cell, overcoming many common challenges faced by drugs based on small molecules or antibodies… whilst also checking toxicity,” she said.
The next stage of research is to check the effectiveness of the inhibitors in preclinical cancer models.
Mason added that it was hope the technology could enable the discovery of other drug candidates able to tackle previously ‘undruggable’ targets.
NEWS: ‘Drugging the undruggable’ will be the theme for Therapeutic Oligonucleotides 2025 conference at the AstraZeneca R&D site in Gothenburg, Sweden from 14–15 May
ELRIG, the not-for-profit organisation for the drug discovery community, announced the keynote speakers for the event will include Rory Johnson, associate professor, at University College Dublin, together with Dr Shalini Andersson, vice president Nucleic Acid Therapeutics at AstraZeneca.
This second ELRIG meeting on therapeutic oligonucleotides features scientists from academia, industry, and other members of the drug discovery community to explore the discovery, validation, and targeting of oligonucleotide-based drug candidates, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA).
Pic: Brano