The pathways that control the behaviour of diseased cells involve complex interactions between large molecules like proteins. Protein-protein interactions (PPIs) represent a vast repertoire of potential targets for new drugs against human diseases. But not all PPIs are suitable as drug targets, and many hundreds of thousands of PPIs occur in human cells. As such, identifying the right PPI target for the development of next-generation drugs is oftentimes akin to looking for a needle in a haystack. Finding better, more efficient ways to discover druggable PPI targets is therefore critical to expand the number of first-in-class drugs for human diseases.

Ashok Venkitaraman’s laboratory has developed a novel approach to PPI target discovery, termed Protein-interference or Protein-i, whereby a library of biologically derived, short, stable peptides is used to hunt for ligands that can disrupt therapeutically important and potentially druggable PPIs. Their study, published in the journal Cell Chemical Biology, illustrates a complete blueprint for Protein-i based drug discovery – from the use of genetic screens to identify potential PPI targets, to their biological validation and structural characterization, and to the subsequent development of small-molecule leads against the PPI target. Using this methodology, the team has identified drug-like small molecules that reactivate via nuclear relocalization the tumour suppressor protein FOXO3a, which is more frequently inactivated by post-translational modification rather than mutation, thereby offering the potential development of additional therapeutic tools targeting this important pathway. More generally, this work opens up a new approach for targeting the estimated 300,000 binary PPIs involving human proteins using an efficient genetic screening technology.

Prof. Venkitaraman, lead author of this study said,

“I am excited to report the development of Protein-i as a new approach for the discovery of druggable PPI targets for human diseases. Protein-i enables the rapid identification of potential sites for the development of first-in-class drugs that target PPIs, including peptides, macrocyclics or small-molecules. I am delighted that the Protein-i approach has been successfully spun-out into industry through the founding of PhoreMost, a start-up biotech based in Cambridge, where it is fuelling new drug discovery by several pharma partners.”