Published in Nature Communications, the study introduces cycloSEL, a platform that enables researchers to screen more than 16 million synthetic macrocycles in a single experiment. By combining large-scale screening with drug-like chemistry, cycloSEL offers a new way to discover compounds against cancer targets that are often considered “undruggable”.

Tackling a long-standing bottleneck

Many cancer-driving proteins lack the deep binding pockets that conventional drugs rely on. Instead, they interact through broad, flat surfaces, making them difficult to target with standard small molecules. As a result, a large part of the human proteome remains inaccessible to current therapies. Macrocycles, molecules that are larger and structurally constrained, offer a promising alternative. They can bind to these challenging surfaces while still holding potential as drug-like compounds. However, discovering macrocycles that are both effective and suitable for use in cells has proven difficult. CycloSEL addresses this challenge by screening fully synthetic macrocycles that are specifically designed to combine strong binding with favorable drug properties.

A different way of screening

What sets cycloSEL apart is its barcode-free approach. Many existing technologies rely on DNA or RNA tags to identify compounds, but these can interfere with how molecules bind to their targets. Instead, cycloSEL uses advanced mass spectrometry and sequencing software to directly identify active compounds from complex mixtures. This allows for a more natural selection process and opens the door to targeting proteins that are difficult to access with existing methods. “The self-encoded library technology developed in our lab over the past few years is very powerful for screening millions of compounds in short timeframes,” says Sebastian J. Pomplun, corresponding author of the study. “I am convinced that the cycloSEL platform will give access to many novel therapeutic candidates for previously undruggable targets.”

Proof of concept in leukemia

To demonstrate its potential, the researchers applied cycloSEL to WDR5, a protein involved in acute myeloid leukemia (AML). WDR5 plays a key role in cancer by coordinating interactions with other proteins, making it an attractive but challenging drug target. From a single screening experiment, the team identified a highly potent macrocycle that binds WDR5 and disrupts its interaction with the leukemia-driving protein MLL. With only minimal optimization, the compound was able to enter cells, remain stable in human serum, and inhibit leukemia cell growth.

Because the library was designed with drug-like properties in mind from the start, the path from discovery to functional compound was significantly faster than in traditional approaches.

Expanding the druggable landscape

The broader impact of cycloSEL lies in its versatility. In principle, the platform can be applied to many different proteins, including those that have so far resisted drug discovery efforts—such as transcription factors and RNA-binding proteins. By enabling the rapid identification of compounds that can engage these targets inside cells, cycloSEL could help expand the range of diseases that can be treated with small-molecule drugs.

From discovery to application

For Oncode Institute, the platform fits closely with its mission to translate scientific insights into tangible impact. The technology offers a powerful approach to identifying new starting points for therapies and has the potential to speed up the development of drugs against targets that have so far remained difficult to address. The team is now actively exploring next steps to scale the platform and maximize its impact, with a clear focus on advancing it toward real-world application and unlocking broader translational and commercial opportunities.

“CycloSEL is an powerful example of how innovative science can unlock entirely new therapeutic opportunities,” says Alexander Turkin, a dedicated Business Developer for the research group of Sebastian J. Pomplun. “It brings us closer to targeting disease mechanisms that were previously out of reach.” 

With CycloSEL, researchers are not only expanding the toolbox for drug discovery, but also reshaping which targets may become druggable in the future.