Cancer research has identified many proteins that play a central role in driving the disease. However, a large number of these remain "undruggable", meaning they cannot be easily targeted by traditional drugs. Why? Because effective drugs usually work by fitting into small crevices or pockets on the surface of a protein, much like a climber gripping onto a mountain face. Some proteins, however, have smooth, featureless surfaces, leaving nothing for a small molecule to latch onto. These proteins, despite being central to cancer biology, remain beyond the reach of current drug strategies. A prime example is the protein Myc, which is overactive in many cancers but still lacks a working drug despite decades of effort.
The goal of our ExploDProteins project was to rethink how we target such proteins. Rather than going after the "slick" proteins directly, we aimed to use the cell's own machinery to remove them altogether. Our idea was to develop bifunctional molecules with one end would act as a signal (such as a small DNA-damaging agent that attracts the cell’s DNA repair systems) while the other end would recruit the protein degradation machinery to dispose of selected proteins that assemble at these damage sites.
As the project evolved, we made several major discoveries and technological advances, some expected, others entirely novel:
We developed a new approach to selectively degrade PI3Kα, a protein frequently mutated in cancer. Even though available drugs bind to multiple related proteins, our method selectively removed just one, solving a long-standing problem in oncology. This work has been patented and licensed to a spin-out company.
We created a unique tool based on a natural DNA repair enzyme called MGMT. By modifying this protein and attaching it to other proteins of interest, we built a switchable degradation system. This means scientists can now study what happens in a cell when any protein is rapidly and precisely removed, a powerful method for discovering how cells work and how diseases progress.
We explored how to degrade a critical DNA repair protein called PALB2, which is especially relevant in cancers like breast, prostate, and uterine cancer. We built new cell models to study this process and identified drug combinations that selectively kill cancer cells lacking PALB2 function. This opens the door to new personalized cancer treatments.
We also demonstrated that antibody-drug conjugates (ADCs) can be used to deliver our protein-degrading molecules directly into cancer cells, combining the precision of immunotherapy with the power of targeted degradation.
In conclusion, the ExploDProteins project has pioneered new strategies to tackle some of the most difficult targets in cancer biology. By combining synthetic chemistry, molecular biology, and drug delivery innovation, we have not only built a toolkit for the next generation of biological research but also created a foundation for a new class of cancer treatments. These treatments work not by simply blocking harmful proteins, but by removing them altogether, offering hope for more selective and less toxic therapies for patients.
