New approach puts hard-to-reach proteins within reach of drug development

22 april 2026

Carlo Verhoef successfully defended his dissertation on April 21 at the Department of Biomedical Engineering at 黑料福利网. His research, carried out within the Chemical Biology group under the supervision of Professor Luc Brunsveld, focused on a new strategy to target proteins that have long been out of reach for medicines, using so-called molecular glues.

Carlo Verhoef. Photo by Angeline Swinkels.

Proteins in the human body are constantly working together. They bind to each other, pass on signals, and regulate processes such as cell growth. In diseases like cancer or diabetes, these processes can go wrong. To intervene, scientists can try to disrupt or strengthen the activity of specific proteins using small molecules, which form the basis of many medicines.

However, some proteins are particularly difficult to reach. They lack a fixed shape, and are so dynamic that conventional drugs struggle to bind effectively. For a long time, this put them out of reach of treatment.

This is exactly the challenge that Verhoef set out to address. One promising solution is molecular glues: small molecules that stick two proteins together and strengthen their interaction. This allows scientists to intervene in biological processes that were previously inaccessible.

Cover of the thesis by Carlo Verhoef.

Verhoef used molecular glue in three ways and advanced the technology further.

Locking proteins in their inactive state. The protein HRAS is often overactive in cancers. It only functions properly when it is in the right location inside the cell: at the cell membrane, the outer layer of the cell. Another protein, PDE6delta, helps transport HRAS there. Verhoef developed molecular glues that stabilized this HRAS/PDE6delta protein-protein interaction and thereby disrupted the signaling activity of HRAS. The binding was made up to 23 times stronger, without affecting other, similar proteins.

Understanding how molecular glue works. For a second type of molecular glue, one that holds the proteins 14-3-3 and Pin1 together, Verhoef mapped the mechanism of action step by step. Using advanced measurement techniques, he showed that the binding proceeded in two steps: first a quick, loose connection, followed by a slower, stronger bond. This kind of insight is important for designing future molecular glues more precisely.

A new approach: molecular glue as a demolition crane. The most innovative contribution was the introduction of MGPROTACs, a hybrid technology that combines molecular glues with targeted protein degradation. The idea: use a molecular glue to hold a disease-causing protein in place, while simultaneously attaching a kind of demolition crane that marks the protein for destruction by the cell itself. As proof of concept, Verhoef designed compounds that guided the hormone receptor protein ERalpha, which is involved in breast cancer, toward such a degradation machine.

In laboratory settings, ERalpha was indeed marked for destruction. Structural analysis revealed why this worked so well: the proteins involved formed a new shared contact surface with many favorable interactions.

Finally, Verhoef tested this strategy on a protein that has no fixed shape: ChREBPalpha, a protein that plays a role in type 2 diabetes. The molecular glue successfully held this elusive protein in place and attracted the degradation machinery. While the glues showed strong binding to ChREBPalpha, the molecules need further optimization for future studies, which is currently being explored.

What does this mean for society?

This research shows that proteins previously considered out of reach can still be targeted therapeutically, through their natural interactions with other proteins. This significantly expands the number of possible targets for new medicines.

In the long run, this approach could contribute to treatments for diseases in which such unreachable proteins play a central role, including cancer and type 2 diabetes. The introduction of MGPROTACs is a particularly promising step: a smart combination of two powerful strategies from molecular medicine.