Protein Degrader Research,

In the ever-evolving landscape of medical research, protein degraders have emerged as a revolutionary class of therapeutic agents. Targeted protein degradation has rapidly expanded as a promising approach in drug discovery, opening up new possibilities for treating diseases that were once considered challenging or even impossible to address.

Understanding Protein Degraders​

Proteolysis-Targeting Chimeras

Proteolysis-Targeting Chimeras are a class of small molecules designed to induce the selective degradation of specific proteins by harnessing the cell’s natural protein degradation machinery. Structurally, a Proteolysis-Targeting Chimera is a bivalent chemical probe. One end binds to an E3 ligase, which is an enzyme in the cell’s ubiquitin-proteasome system. The other end binds to a protein of interest (POI). Once the Proteolysis-Targeting Chimera binds to both the E3 ligase and the POI, it brings them into close proximity. This proximity leads to the ubiquitination of the POI. Ubiquitination is a process where small proteins called ubiquitins are attached to the target protein. The ubiquitinated protein is then recognized and degraded by the proteasome, which is like a cellular garbage disposal system.​

This strategy is highly significant as it enables the precise and selective degradation of target proteins. Many proteins that are involved in disease processes are difficult or impossible to inhibit using traditional methods. For example, some proteins lack well-defined active sites that can be targeted by small-molecule inhibitors. Proteolysis-Targeting Chimeras, however, do not rely on binding to an active site. They can target these so-called “undruggable” proteins by simply binding to any accessible region on the protein surface. By harnessing the inherent process of protein degradation within cells, Proteolysis-Targeting Chimeras offer a highly specific mechanism to eliminate target proteins.

Molecular Glues

Molecular glues are monovalent small molecules that promote novel protein-protein interactions. They function by binding to distinct sites on two separate proteins. This binding leads to changes in the structure or function of the proteins, ultimately resulting in the ubiquitination of the POI and its subsequent degradation by the proteasome.​

Molecular glues are different from Proteolysis-Targeting Chimeras in their structure. While Proteolysis-Targeting Chimeras are bivalent molecules with two distinct binding domains, molecular glues are smaller and monovalent. They work by subtly altering the protein-protein interaction landscape in the cell. For instance, they might bind to an E3 ligase and induce a conformational change in it. This conformational change allows the E3 ligase to interact with a POI that it normally would not bind to. Once this new interaction is formed, the POI is marked for degradation. Elucidating the structures of molecular glue complexes provides valuable insights into the conformational changes and intermolecular interactions that occur upon binding. By visualizing these complexes, researchers can better understand how molecular glues work and how they can be optimized for therapeutic use.

Applications of Protein Degraders in Disease Treatment

Cancer

Cancer is one of the main areas where protein degradants are extensively studied. Many proteins involved in the growth, survival and metastasis of cancer cells are potential targets of degradation. For example, in breast cancer, proteins such as the estrogen receptor (ER) have been targeted by protein decomposition targeting Chimeras. In 2025, Arvinas and Pfizer made significant progress in proteolysis of the targeted Chimera drug vedegestrant. In a pivotal phase 3 clinical trial involving HR-positive, HER2-negative breast cancer patients with ESM1 mutations, the VEGI cohort showed significant results. It reduces the risk of disease progression or death by more than 40% compared to active controls. This is a big step forward as it demonstrates the efficacy of proteolysis targeting Chimera in the real world against major cancer types.

Another example is blood cancer. B-cell malignancies, such as chronic lymphoblastic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), are being targeted by protein degradants. For example, some proteolytic targeting inlays and molecular gels are designed to target Bruton’s casein (BTK), a key protein in the B cell receptor signaling pathway. At the EHA 2025 meeting, Bristol Myers Squibb introduced the updated clinical study results of its oral E3 ubiquitin ligase brain cell modulator (CELMoD) drugs mecidomide and ibodominium in patients with multiple bone marrow (MM) tumors, as well as the research progress of gorcamide in non-Hodgkin tumors (NHL) research. Golcadomide combined with lidocaine has shown significant efficacy in the treatment of patients with recurrent/catastrophic glaucoma tumors, with an overall cure rate (ORR) of 94% and a complete cure rate (CR) of 63%. This suggests the potential of protein degradants in treating hematological malignancies and improving patient outcomes.

Fig.1 Ubiquitin Signaling’s Role in the Tumor Microenvironment.1

Neurodegenerative Disorders

Neurodegenerative disorders like Alzheimer’s and Parkinson’s disease are also in the spotlight for protein degrader-based therapies. In these diseases, the accumulation of misfolded or abnormal proteins is a key pathological feature. For example, in Alzheimer’s disease, the tau protein forms abnormal aggregates. Protein degraders could potentially be designed to target and degrade these abnormal tau proteins, preventing their aggregation and the subsequent neurodegeneration. Some pre-clinical studies are already exploring the use of Proteolysis-Targeting Chimeras and molecular glues to target proteins involved in neurodegenerative pathways. Although still in the early stages, this research holds great promise for developing effective treatments for these currently incurable diseases.

Autoimmune Diseases

Autoimmune disease occurs when the body’s immune system mistakenly attacks its own tissues. Protein degradants can play a role in regulating immune responses. For example, some proteins involved in immune cell activation can be targets for degradation. Kymera Therapeutics’ STAT6 reducing agent KT-621 has achieved positive results in a Phase 1 clinical trial in healthy testers. In addition，the patient was not received any dosage of KT-621，but the patient was not received any dosage. STAT6 is a key protein in the immune signaling pathway, and its degradation may help treat autoimmune diseases where the pathway is over-activated.

Cryo-EM: A Powerful Tool for Studying Protein Degraders​

When it comes to understanding the structure and function of protein degraders, cryo-electron microscopy (cryo-EM) has emerged as a powerful tool. For multi-component complexes like Proteolysis-Targeting Chimeras and molecular glues, cryo-EM offers unique advantages over traditional techniques such as X-ray crystallography (XRC) and nuclear magnetic resonance (NMR).​

Cryo-EM allows for the observation of these complexes in their native state. This is crucial because it reveals the different states and conformational changes that the complexes can adopt. In contrast, XRC often requires the protein complex to be crystallized, which can sometimes alter the native structure. NMR has limitations in terms of the size of the complexes it can study. Cryo-EM can provide high-resolution structures of protein degraders and their associated complexes. This high-resolution information allows researchers to better understand the intricate details of the interactions between the components of protein degraders, such as how the E3 ligase and the POI interact when bridged by a Proteolysis-Targeting Chimera or how a molecular glue induces new protein-protein interactions.​

By understanding these structural details, structural biologists can optimize the design of protein degraders. They can make modifications to enhance the efficacy and specificity of the degraders. For example, they might adjust the length or chemical properties of the linker in a Proteolysis-Targeting Chimera to improve the proximity-induced ubiquitination process. In the case of molecular glues, they can design molecules that more effectively induce the desired conformational changes in the target proteins. This understanding also paves the way for the development of novel therapeutics. By having a clear picture of how protein degraders work at the molecular level, researchers can rationally design new molecules with improved properties.​

Future Directions and Challenges​

The field of protein degraders is still in its relative infancy, but the potential is enormous. One of the future directions is the development of more selective and potent protein degraders. As of now, while there has been significant progress, there is still room for improvement in terms of ensuring that only the target proteins are degraded and minimizing off-target effects.​

Another area of focus is the development of protein degraders that can target extracellular or membrane proteins. Current Proteolysis-Targeting Chimeras and molecular glues mainly target intracellular proteins. However, many disease-relevant proteins are located on the cell surface or in the extracellular space. New strategies such as the development of cell-surface-targeting Proteolysis-Targeting Chimeras or molecular glues are being explored.​

There are also challenges in the development process. Protein degraders often have complex structures, which can lead to issues with solubility, pharmacokinetics, and bioavailability. For example, some Proteolysis-Targeting Chimeras have low solubility, which can affect their ability to be formulated into drugs. Additionally, the cost of developing and manufacturing protein degraders can be high due to their complexity. Overcoming these challenges will require continued research and innovation in the fields of chemistry, biology, and pharmaceutical sciences.​

In conclusion, protein degraders represent a paradigm-shifting approach in drug discovery. They have the potential to revolutionize the treatment of a wide range of diseases, from cancer to neurodegenerative and autoimmune disorders. With ongoing research, technological advancements like cryo-EM, and a growing understanding of the underlying biology, the future of protein degraders in medicine looks very promising.

 

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Reference

Lauriola, Angela, et al. “Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy.” Cancers 15.11 (2023): 3009. https://doi.org/10.3390/cancers15113009