Periodic Reporting for period 4 - ExploDProteins (Exploiting the DNA damage response to induce degradation of proteins)
Okres sprawozdawczy: 2024-12-01 do 2025-05-31
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.
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.
The ExploDProteins project aimed to harness the cell’s natural DNA damage response to induce targeted protein degradation, with the broader goal of addressing so-called “undruggable” proteins.
Aim 1: Targeted Degradation of Lipid Kinases
While the original goal was to degrade DNA damage response proteins, the project unexpectedly uncovered a selective degrader of PI3Kα, a key oncogenic kinase. Notably, we demonstrated that although the molecule binds multiple PI3K isoforms, it selectively triggers degradation of only PI3Kα—a result that was both surprising and scientifically significant.
This discovery was published in Chemical Science and has since formed the foundation for a translational effort, including patent protection and commercial development in the form of a spin-out company. We further enhanced this approach by developing antibody-drug conjugates that deliver these degraders specifically to cancer cells, offering improved therapeutic selectivity with reduced off-target effects.
Aim 2: MGMT as a Platform for Protein Degradation
We applied the DNA repair enzyme MGMT as a new inducible protein degradation system. By fusing MGMT to a protein of interest, we enabled the degradation of that fusion protein on demand with a small molecule. This approach was published in ACS Chemical Biology and is already being used to study dynamic protein function.
Additionally, we have initiated a collaboration with a crop protection company to explore applications of this technology in agricultural science.
Aim 3: Functional Targeting of PALB2
PALB2 is an essential player in DNA repair and a candidate vulnerability in certain cancers. We developed a novel inducible cell line to study the biological effects of degrading PALB2 and identified synthetic lethal interactions that could inform new therapeutic strategies. We also created the first high-affinity peptide for studying PALB2-BRCA2 interactions, which has advanced understanding of this protein complex.
Across the course of the project, we have delivered:
Three major technological platforms: selective degraders of PI3Kα, MGMT-based fusion degraders, and PALB2-targeting tools.
High-impact scientific publications, including in Chemical Science and two papers ACS Chemical Biology, with further manuscripts underway.
Commercial exploitation of results, with intellectual property filings and active industry engagement.
Cross-disciplinary outreach, including collaboration with a crop protection company, showcasing broader applications of our molecular tools.
In summary, ExploDProteins has fulfilled and surpassed its original aims, generating novel insights, innovative tools, and real-world opportunities across oncology, biology, and beyond.
Aim 1: Targeted Degradation of Lipid Kinases
While the original goal was to degrade DNA damage response proteins, the project unexpectedly uncovered a selective degrader of PI3Kα, a key oncogenic kinase. Notably, we demonstrated that although the molecule binds multiple PI3K isoforms, it selectively triggers degradation of only PI3Kα—a result that was both surprising and scientifically significant.
This discovery was published in Chemical Science and has since formed the foundation for a translational effort, including patent protection and commercial development in the form of a spin-out company. We further enhanced this approach by developing antibody-drug conjugates that deliver these degraders specifically to cancer cells, offering improved therapeutic selectivity with reduced off-target effects.
Aim 2: MGMT as a Platform for Protein Degradation
We applied the DNA repair enzyme MGMT as a new inducible protein degradation system. By fusing MGMT to a protein of interest, we enabled the degradation of that fusion protein on demand with a small molecule. This approach was published in ACS Chemical Biology and is already being used to study dynamic protein function.
Additionally, we have initiated a collaboration with a crop protection company to explore applications of this technology in agricultural science.
Aim 3: Functional Targeting of PALB2
PALB2 is an essential player in DNA repair and a candidate vulnerability in certain cancers. We developed a novel inducible cell line to study the biological effects of degrading PALB2 and identified synthetic lethal interactions that could inform new therapeutic strategies. We also created the first high-affinity peptide for studying PALB2-BRCA2 interactions, which has advanced understanding of this protein complex.
Across the course of the project, we have delivered:
Three major technological platforms: selective degraders of PI3Kα, MGMT-based fusion degraders, and PALB2-targeting tools.
High-impact scientific publications, including in Chemical Science and two papers ACS Chemical Biology, with further manuscripts underway.
Commercial exploitation of results, with intellectual property filings and active industry engagement.
Cross-disciplinary outreach, including collaboration with a crop protection company, showcasing broader applications of our molecular tools.
In summary, ExploDProteins has fulfilled and surpassed its original aims, generating novel insights, innovative tools, and real-world opportunities across oncology, biology, and beyond.
The ExploDProteins project has advanced beyond the current state of the art in targeted protein degradation. Our work introduces new molecular strategies that bypass the limitations of conventional small-molecule drugs, which typically rely on binding to active sites - an approach that fails for many so-called “undruggable” proteins.
By focusing instead on protein assemblies and cellular degradation pathways, we developed methods to eliminate entire protein complexes or specific protein isoforms, rather than simply inhibiting them. This represents a fundamentally new direction in drug discovery, particularly relevant for cancer and other complex diseases.
Key breakthroughs include:
A selective degrader of PI3Kα, overcoming a decades-long challenge in oncology by achieving isoform-specific degradation without affecting closely related kinases.
An innovative MGMT-based fusion and small-molecule degron system, giving researchers a fast, precise, and druggable way to induce degradation of nearly any protein.
New tools for dissecting PALB2 biology, with potential to inform targeted treatments for cancers that rely heavily on homologous recombination repair.
These results not only introduce new technologies to basic research but also provide validated platforms for future therapeutic development. The project has already resulted in publications, patents, and commercial partnerships, and its outputs are expected to continue influencing both academic and translational science well beyond the grant period.
By focusing instead on protein assemblies and cellular degradation pathways, we developed methods to eliminate entire protein complexes or specific protein isoforms, rather than simply inhibiting them. This represents a fundamentally new direction in drug discovery, particularly relevant for cancer and other complex diseases.
Key breakthroughs include:
A selective degrader of PI3Kα, overcoming a decades-long challenge in oncology by achieving isoform-specific degradation without affecting closely related kinases.
An innovative MGMT-based fusion and small-molecule degron system, giving researchers a fast, precise, and druggable way to induce degradation of nearly any protein.
New tools for dissecting PALB2 biology, with potential to inform targeted treatments for cancers that rely heavily on homologous recombination repair.
These results not only introduce new technologies to basic research but also provide validated platforms for future therapeutic development. The project has already resulted in publications, patents, and commercial partnerships, and its outputs are expected to continue influencing both academic and translational science well beyond the grant period.