Georg Winter

Throughout his career, Georg Winter has been inspired by opportunities that emerge from looking at biology through the lens of small molecules. Small molecules not only represent a universal currency for biological communication, controlling processes from quorum sensing in bacteria to neurotransmission in humans, but also form the foundation of 80% of all approved medicines. A major limitation of small molecules as medicines is their anticipated limited reach within the human proteome. It is frequently presumed that only approximately 20% of all human proteins can be pursued with small molecules, leaving some of the most compelling therapeutic targets unactionable. 

Over the last 10 years, Georg Winter's group has focused on challenging this dogma, trying to reimagine molecular design of small molecules by connecting synthetic chemistry with high-throughput biological experimentation. Conceptually, the team takes inspiration from small molecules designed by nature, including phytohormones such as auxin or abscisic acid. These compounds function by inducing proximity between an effector and a target protein, leading either to inhibition or degradation of the target protein. Hence, they act as chemical neomorphs that functionally rewire an effector protein to alter the fate of a protein target. Proximity induction is a fundamental regulatory principle in biology that governs almost all cellular processes from transcription to signal transduction. It is hence not surprising that evolution has frequently re-discovered small molecule-induced proximity induction as a strategy to modulate biological circuits. With few exceptions, this design principle has however been ignored in the innovation of new medicines. 

A central thesis of the groups research is that controlling proximity will enable us to control biology. They believe that organizing the design of future medicines around proximity induction as a guiding principle will enable us to move beyond target inhibition but instead empower us to program biology beyond evolutionary constraints, thereby finding novel therapeutic solutions for some of the most urgent medical challenges. To that goal, a core focus of the group has been a concept called targeted protein degradation (TPD). In this field, they aim to reprogram the activity of the ubiquitin-proteasome system by small molecule “degraders” that act as chemical neomorphs by altering the activity of E3 ubiquitin ligases.

Targeted Protein Degradation (TPD): Dissection and Chemical Reprogramming of E3 Ligases

The emerging field of TPD hinges on small molecule “degraders” that bring an E3 ubiquitin ligase into close proximity with a target protein, leading to target ubiquitination and subsequent degradation. Degraders, therefore, function as chemical neomorphs, conferring novel substrate specificity to E3 ligases and enabling the degradation of proteins they would not naturally recognize.

In 2015, the Winter Lab introduced the first chemical solution to in vivo target protein degradation, by developing heterobifunctional chemical degraders (“PROTACs”) that co-opt the E3 ligase CRBN (Winter, Buckley Science 2015). This discovery helped drive the rapid expansion of the TPD field, sparking broad interest and development efforts in both academia and the biopharmaceutical industry. Their ensuing studies have demonstrated that TPD provides unique advantages over conventional inhibitors such as increased potency and selectivity. While there has been significant enthusiasm in academia and industry surrounding PROTACs, they have limitations in addressing truly undruggable targets. PROTACs rely on the presence of a potent small-molecule binder for the target protein, which poses significant challenges for transcription factors and related gene-regulatory effectors, as well as for other disordered proteins that drive human diseases. 

To overcome these limitations, Georg Winter's group focuses on another class of small-molecule degraders known as molecular glue degraders (MGDs). At the time, the only known MGDs were the phytohormone auxin and the clinically approved anti-myeloma drugs lenalidomide and related immunomodulatory imide drugs (IMiDs). Mechanistically, MGDs bind to an E3 ligase, altering its surface topology to recruit target proteins, such as the transcription factors IKZF1 and IKZF3, for degradation. Notably, MGDs lack measurable affinity for the degraded target in isolation, highlighting their potential to achieve the goal of "degrading the undruggable." Despite this promise, the field faced a significant bottleneck: the discovery of MGDs had been entirely serendipitous, with no rational discovery strategies in place. This is a gap that the group's research addresses by combining functional genomics and proteomics. Among others, this allowed them to unlock novel ligases for TPD (Kagiou, Nature Communications 2024) or identify intramolecular bivalent glue degraders as novel and differentiated modality in TPD (Hsia, Hinterndorfer, Cowan, Nature 2024). In sum, their work has thus opened several new avenues for the systematic exploration and development of MGDs. 

Discovery of New Strategies to Rewire Cancer by Chemical Genetics and Chemoproteomics

Equipped with a strong expertise and rich toolbox from their work in TPD, Georg Winter's group is now exploring the concept of chemical neomorphs beyond the ubiquitin-proteasome system and, in general, beyond loss of function (LOF) approaches. Supported by an ERC Consolidator Grant, they will focus on the discovery of small-molecule strategies to rewire oncogenic transcription regulation and to reprogram the DNA damage response. Towards that goal, they are relying on two key enabling technologies: functional genomics and high-throughput proteomics. They have integrated pooled genome-wide CRISPR/Cas9 screens with flexible functional readouts and deep mutational scanning. This allows them to survey the entire genome while zooming in on the individual function of proteins at a single amino acid resolution. Moreover, they routinely leverage proteomics to understand how small molecules interface with the (human) proteome in an unbiased manner. Producing large-scale chemical proteomics datasets and connecting them to Artificial Intelligence allowed them to even predict how small molecules would interact with native biological systems using simply the chemical structure as input (Offensperger, Tin, Duran-Frigola, Science 2024).

Georg Winter, PhD, performed his graduate studies at CeMM, working on elucidating the mechanism of action of cancer drugs under the supervision of Giulio Superti-Furga. He continued his training in chemical biology, working as a postdoctoral fellow with Dr. James Bradner the Dana Farber Cancer Institute/Harvard Medical school where he published the first paper reporting on in vivo target protein degradation (Winter et al., Science 2015). He was recruited as a CeMM Principal Investigator in June 2016. Since 2025, Dr. Winter is the Life Science Director of AITHYRA, a new Research Institute for Biomedical AI. Thematically, his lab works at the interface of chemical biology, cancer and gene control. Dr. Winter’s research has led to the incorporation of C4 Therapeutics, moreover, he is a scientific co-founder of Proxygen and Solgate Therapeutics. His group is supported by several national and international grants and fellowships including ERC Grants (Starting and Consolidator), an Aspire Award from the Mark Foundation and a Cancer Grand Challenge Grant. Dr. Winter’s contributions to the field of targeted protein degradation were acknowledged via multiple prices and awards, including the Tetrahedron Young Investigator Award, the Wilson S. Stone Memorial Award from MD Anderson, the Eppendorf Award for European Scientists, and the Elisabeth Lutz Award of the Austrian Academy of Sciences.

Offensperger F, et. al. Large-scale chemoproteomics expedites ligand discovery and predicts ligand behaviour in cells. Science 2024 Apr 26;384(6694):eadk5864. (abstract)

Hsia O, et al. Targeted protein degradation via intramolecular bivalent glues. Nature. 2024 Mar;627(8002):204-211. (abstract)

Hanzl A, et al. Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders. Nature Chemical Biology. 2022 Nov 3. (abstract)

Mayor-Ruiz C, et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nature Chemical Biology, 2020 Aug 3. (abstract)

Winter GE, et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19;348(6241):1376-81. (abstract)