Nuage Therapeutics, the spin-off seeking to turn previously “intractable” proteins into new cancer treatments

For decades, some of the proteins involved in diseases such as cancer, Alzheimer's, and Parkinson's have remained beyond the reach of traditional medicines. Although researchers understood the role these proteins played in the development of certain diseases, their flexible and changing structure made it extremely difficult to design drugs capable of acting on them, to the point that many were considered “intractable.”

That is the challenge Nuage Therapeutics aims to address. The Barcelona-based biotech company, which emerged as a spin-off from researcher Xavier Salvatella's laboratory at the Institute for Research in Biomedicine (IRB Barcelona) and ICREA, and is currently headquartered at the Parc Científic de Barcelona, has developed its own technological platform to discover new drugs targeting this type of protein, known as intrinsically disordered proteins (IDPs). Its technology seeks to enable the development of drugs capable of acting on proteins that until now had been beyond the reach of the pharmaceutical industry.

To understand why these proteins have been so difficult to target with drugs, one must focus on a characteristic that makes them particularly distinctive: their very nature. Unlike many proteins, which maintain a relatively stable three-dimensional structure that drugs can target, intrinsically disordered proteins do not have a fixed structure. The relevance of these proteins, however, is considerable: it is estimated that around 40% of human proteins contain disordered regions, many of which are involved in diseases such as cancer and Alzheimer's.

This difficulty is precisely the challenge Nuage Therapeutics seeks to overcome. The company initially focuses on transcription factors, a group of intrinsically disordered proteins that play a key role in the development of different types of cancer. One of Nuage Therapeutics' first targets is ASCL1, a transcription factor involved in the development and progression of small cell lung cancer (SCLC). It is an especially aggressive form of lung cancer, for which therapeutic options remain limited and survival rates have barely improved in recent decades.

It is precisely in these tumors that Nuage Therapeutics seeks to advance, developing new therapies capable of targeting proteins that have so far been difficult to address with traditional drugs. However, the success of this first therapy focused on ASCL1 would only be the beginning. “If we manage to demonstrate that this approach works, we will not only be validating a drug, but a completely new way of discovering drugs,” says Stuart Hughes, CEO of the company. A strategy that, beyond this first program focused on ASCL1, could be applied to other types of cancer and, in the future, even to neurodegenerative diseases such as Alzheimer's.

From laboratory to market

But reaching this point has required years of research. Although Nuage Therapeutics was formally established in 2021, the company's origins date back several years, to the research of biophysicist Xavier Salvatella, who leads the Molecular Biophysics Laboratory at IRB Barcelona. Working with the androgen receptor, a protein involved in prostate cancer, Salvatella's team managed to demonstrate, for the first time, that a small molecule could bind to an intrinsically disordered protein by taking advantage of moments when it temporarily adopted a more stable structure.

This finding represented a paradigm shift, as drugs can only exert their effect if they first manage to bind to the protein they are designed to target. Until then, it was assumed that the flexible and changing nature of this type of protein prevented such binding and, therefore, made it impossible to develop drugs targeting them.

That scientific discovery became the starting point for Nuage Therapeutics. The company's challenge then became to transform that scientific finding into a technological platform capable of identifying the moments when these disordered proteins temporarily adopt a more stable conformation. It is during these moments that drugs can bind to them and act, opening the door to developing medicines against proteins that until then had been beyond the reach of traditional drug discovery techniques.

“What we did was transform truly innovative academic science into an efficient and unique drug discovery engine,” explains Hughes. To achieve this, Nuage Therapeutics developed a set of proprietary technologies that make it possible to identify these transient states of intrinsically disordered proteins when they temporarily adopt a more stable form. It is precisely during these moments that a drug can bind to the protein and modify its activity.

The first challenge: one of the most aggressive lung cancers

The next challenge is to clinically validate this new drug discovery approach, that is, to demonstrate that it can be translated into a safe and effective treatment for patients. Nuage Therapeutics' technology would thus turn a characteristic that for decades was considered a limitation—the changing structure of these proteins—into an opportunity to develop new treatments against diseases in which these proteins play a key role and for which treatment options remain limited

One of the most promising characteristics of these new drugs is that they can primarily target cancer cells while affecting healthy tissues to a lesser extent

In the case of ASCL1, one of the transcription factors Nuage Therapeutics is working on—and which is involved in the development of small cell lung cancer—the company has already identified molecules capable of binding to this protein and modifying its activity. The next step is to optimize these molecules to turn them into drug candidates and, subsequently, evaluate their safety and efficacy in patients. The ultimate goal is for this work to lead to a new therapeutic option for patients with this type of cancer.

One of the most promising characteristics of the potential new drugs targeting ASCL1 that Nuage Therapeutics is developing is their ability to act more specifically on tumor cells. The idea is that these treatments could primarily target cancer cells while affecting healthy tissues to a lesser extent. This could represent an advantage over current therapies, such as conventional chemotherapy, which can also damage healthy cells and cause significant side effects

However, several steps remain before this possibility can become a treatment for patients. The molecules will have to go through different stages of development and clinical trials, a process that could take several years before a potential treatment reaches patients.

Although this program for small cell lung cancer is the most advanced in the company's pipeline, Nuage Therapeutics insists that its value goes beyond developing a single drug. The biotechnology company's aim is to demonstrate that its technology allows the development of drugs against proteins that until now were considered “intractable,” and thus open up new treatment possibilities. “Our priority in the coming years is to achieve a first clinical proof of concept showing that this approach works with a drug targeting an intrinsically disordered protein. If we succeed, we could open a new therapeutic frontier,” says Hughes.

Nuage Therapeutics aims to extend this same technology beyond cancer, to neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as inflammatory diseases

Thus, the company is already working on other transcription factors, such as KLF5, a protein involved in different types of cancer, including colorectal, pancreatic, gastric, and esophageal cancers, as well as other tumors of the digestive system.

In the longer term, Nuage Therapeutics aims to extend this same technology beyond cancer. Its platform could be applied to other diseases in which intrinsically disordered proteins play a relevant role, including neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as inflammatory diseases.