The biotech mapping thousands of hidden therapeutic clues

Drug discovery often pushes the boundaries of what we understand. John Lepore, MD, CEO of ProFound Therapeutics and CEO-Partner at Flagship Pioneering, is furthering that challenge by redefining where and how we search for new medicines.

“I was increasingly drawn to understanding the underlying biology of disease at a molecular level – the ‘why’ – and how we might harness science to create better medicines for patients,” Lepore says. After nearly two decades at GSK, where he served as Head of Research, he left to take a bold leap into the unknown: the expanded human proteome.

At ProFound, Lepore leads a team investigating one of biology’s least explored frontiers – the expanded proteome. The tenet on which their studies revolve is both simple and potentially transformative: the possibility that more of the human genome is translated into proteins than previously recognised. Tens of thousands of previously unknown proteins, hiding in plain sight, may hold the key to a new generation of precision medicines.

A tech-powered telescope for the cellular world

At the heart of ProFound Therapeutics is its ProFoundry™ Platform. Powered by RiboSeq, multiomics and advanced AI/ML, it captures a real-time snapshot of protein translation inside human cells. The result? A dynamic view of biology that far outpaces traditional discovery models.

“RiboSeq technology gives us a dynamic, real-time snapshot of all of the proteins that are being translated in a cell,” Lepore explains. This allows the team to spot previously unannotated proteins and study them across multiple biological dimensions – from structure to function, from RNA expression to genetic association.

The integration of machine learning enables the team to predict which novel proteins are most likely to play critical roles in disease – all before any laboratory work begins. This approach accelerates discovery by focusing experimental efforts where the data suggests the highest potential impact.

“This contrasts with the historical approach of studying each protein one at a time,” says Lepore. Instead, ProFound prioritises only the most promising candidates, applying wet lab resources where the computational insights say it matters most.

Where science meets strategy

The discovery of tens of thousands of novel proteins presents a clear challenge of determining which to prioritise.

“We are laser-focused on studying proteins with the highest likelihood of having a significant impact for patients,” he says. By mapping known genetic mutations to these novel proteins, ProFound can identify those with clear associations to disease – significantly increasing the probability that targeting them could lead to breakthrough therapies.

“Medicines directed against these novel, genetically validated proteins hold promise to have a much higher probability of leading to transformational therapeutic effects for patients,” Lepore explains.

From theory to therapy

This approach is already delivering promising insights across key therapeutic areas. Lepore highlights strong early progress in oncology, immunology and metabolic diseases, where ProFound has identified novel cytokines, transmembrane tumour antigens and secreted metabolic regulators with significant therapeutic potential.

And the big players are taking notice. In June 2024, ProFound entered into a landmark partnership with Pfizer and Pioneering Medicines to leverage its platform against obesity – drawn from the largely untapped biology of the expanded proteome.

Despite the power of next-generation technologies, the scale of discovery remains a challenge. With thousands of novel proteins identified – each with potential therapeutic value – the critical task is determining which are most worthy of thorough investigation.

“We have solved this by using advanced computational methods and machine learning to analyse our vast databases,” Lepore says.

What tomorrow holds

So where does Lepore see all this going in the next five to 10 years? AI and machine learning, he says, are still just getting started.

“Today, they are already helping us sift through vast biological datasets, identify patterns that humans might miss, and generate new hypotheses,” Lepore explains. But the horizon is much wider.

He points to AlphaFold’s impact on protein structure prediction as a glimpse of what is coming. “As the tools mature, we will see more integration between computational prediction and experimental validation,” he says. The result? Faster, smarter, more confident progression from data to drug.

And ProFound is ready. With its curated, searchable and genetically anchored dataset, the company is ideally positioned to ride the AI wave into the next generation of therapeutics.

When it comes to precision medicine, Lepore sees not just potential but inevitability. Today’s broad-spectrum drugs often miss the mark, especially for chronic diseases like COPD or heart failure. These are not singular conditions but syndromes driven by a diversity of molecular mechanisms.

“The promise of precision medicine is to identify these discrete mechanisms, develop drugs that specifically target each one, and then administer each molecularly distinct drug to the corresponding patient sub-population,” he says.

But here is the snag: the molecular mechanisms underpinning many of these diseases remain a mystery. But this is the problem ProFound is built to solve.

“We believe the novel proteins we are identifying will reveal many of the ‘missing links’ in understanding the molecular basis of disease,” Lepore says. That means more targeted therapies, higher efficacy and better patient outcomes. Real, personalised medicine, not just marketing.

From curiosity to cure

At the core of it all is a deeply human motivation. Lepore is not just chasing the next breakthrough; his whole career, from the clinic to the boardroom, has been about helping people.

“Throughout my career, I have looked for opportunities where I could apply my skills and energy to have the greatest impact for patients,” he says.

Now, at ProFound, he is guiding a company that could truly redefine what drug discovery means.

By revealing thousands of previously hidden proteins he is redefining the scope of the human proteome, bringing the promise of precision medicine within reach – with the patient at the heart of it all.

“At ProFound, we are making incredible progress towards this vision and look forward to pioneering this brighter future for patients.” And honestly? It sounds like they just might.