Imagine proteins within our body as vehicles in a busy city. Scratches, bumps and even serious accidents may happen. And just like vehicles, proteins are not designed to last forever; malfunctions and breakdowns are to be expected. To keep the city bustling, our body constantly breaks down old or malfunctioning proteins and replaces them with fresh copies.1-4 Researchers have been evaluating how to use this natural housekeeping process for a targeted degradation of disease-causing proteins.5-9
“Watching recent advancements in targeted protein degradation has been incredibly exciting,” says Chris Helal, Head of Synthetic Medicine Design at Biogen. “These molecules add a new and distinct biochemical approach to drugging disease-causing proteins to our repertoire of modalities and hold great promise for the development of new medicines.”
Neutralizing disease-causing proteins effectively and conveniently
Continuous innovation in medicinal chemistry and greater understanding of the natural cycle of proteins in our body are enabling scientists to create potent degrader molecules that can effectively target central proteins in critical pathways in a variety of diseases.5-9
Biogen is advancing targeted protein degradation (TPD) in neurodegenerative diseases (such as Alzheimer’s disease) and immune-mediated and rare diseases. We see great potential to modify these diseases more effectively or selectively, with the potential for a better safety profile or more convenient dosing or route of administration than with currently available drug modalities.
TPD differs from functional inhibition as a single degrader molecule can facilitate the removal of many copies of a disease-causing protein, potentially leading to significantly enhanced potency. Additionally, a degrader can be more efficacious as it can impact both direct function and signaling processes driven by the protein structure (scaffolding effects), and may engender higher selectivity. TPD may also enable removing disease-causing proteins that have no binding pocket for inhibitors and may be more easily reversible than knockdown at the gene level.5-9
Innovating together
“Unlocking the potential of protein degraders requires deep scientific understanding and innovation in different areas of biology and chemistry,” says Chris. “One scientist, one team, or one company can only do so much. That’s why we take a hard look at areas where we are ahead and then partner with others in areas where they are further advanced so we can be better and faster together than any of us could be alone.”
Biogen’s collaborations in TPD began in 2019 with a partnership with C4 Therapeutics, focusing on bifunctional protein degraders called proteolysis targeting chimeras (PROTACs), compounds consisting of two distinct functional groups, a protein inhibitor and a TPD-triggering binder, linked together in one molecule. “Combining our deep understanding of disease biology and robust experience in developing potent protein inhibitors with C4’s strong expertise in creating novel TPD-triggering ligands has yielded molecules with promising therapeutic potential,” says Chris, five years into the partnership.
In October 2024, Biogen took TPD a step further by entering a partnership with Neomorph. Together, the companies will advance small molecule molecular glue degraders (MGDs) to unlock priority targets in Alzheimer’s disease and rare neurological and immunological diseases. Biogen brings a deep understanding of disease biology, promising targets for disease modification, and drug discovery expertise, while Neomorph has a strong platform to create and screen MGDs and identify promising hits.
Unlike PROTACs, MGDs aim to unite protein targeting and degradation machinery without the need to link two distinct functional groups, allowing for smaller molecules. The smaller size makes MGDs more favorable for oral administration and brain penetration than PROTACs or other modalities like antibodies, oligonucleotides, or gene therapies.8-9
“Ultimately, it is all about reaching disease modifying targets in the most efficacious, safest and convenient way”, says Chris. “It is inspiring and fulfilling to advance protein degraders toward that goal for both patients and Biogen, bringing together internal and external strengths.”
Drug Architect Chris Helal
Vice President, Head of Synthetic Medicine Design
As a college sophomore in chemistry, Chris was fascinated by a lecture on crown ethers, cyclic organic molecules that can accelerate chemical reactions. Crown ethers can bind metal ions and then massively accelerate chemical reactions between molecules in different phases—reactions that otherwise would not be possible.
When Chris saw how chemists had carefully designed crown ethers to optimize their catalytic properties, he knew that he also wanted to create molecules with important functions. This area of study became the focus of his doctorate work, and again as he became a pharmaceutical researcher. For Chris, the most important function of a molecule is it’s potential ability to halt or cure disease.
As the Head of Synthetic Medicine Design at Biogen, Chris oversees the company’s work in synthetic modalities including small molecules, oligonucleotides, peptides, linkers and more. Previously, Chris spent five years at Biogen as Head of Medicinal Chemistry. Chris joined Biogen after a 22-year career at Pfizer where he held various roles in Medicinal Chemistry, helping to discover 15 different drug candidates. Chris obtained his Ph.D. in Organic Chemistry from Harvard University, under the guidance of Nobel Laureate Elias J. Corey, and his B.S. in Chemistry, Summa Cum Laude and with Honors from The Ohio State University.
The next horizon
While the targeted degradation of intracellular proteins is currently more advanced than the targeted degradation of extracellular proteins10, Biogen is excited about the ongoing innovation in this area. The Research team closely follows various approaches that leverage antibodies and cell receptors to enable targeted degradation of extracellular proteins. These approaches may be particularly well suited for the treatment of autoimmune diseases, an area where Biogen sees great potential and ongoing need for innovation for patients.
Targeted degradation of intracellular proteins with chimeras and molecular glues
The ubiquitin−proteasome system (UPS) is a major mechanism for the degradation of proteins inside of cells. Certain enzymes (E3 ubiquitin ligases) mark proteins for degradation by the UPS by attaching ubiquitin to them. Researchers are advancing two types of rationally designed molecules to recruit an E3 ubiquitin ligase and trigger the targeted degradation of disease-causing proteins1-4:
- proteolysis targeting chimeras (PROTACs)
- molecular glue degraders (MGDs)
PROTACs consist of two functional components joined by a flexible linker. One component, the protein binder, attaches to the binding pocket of the protein to be degraded, while the other component, the E3 binder, recruits an E3 ubiquitin ligase. This modular structure allows for the rational design of binders that can selectively target a protein of interest. However, it may be difficult to design binders for certain disease-causing proteins.5-7
MGDs are small molecules that ‘glue’ proteins and E3 ubiquitin ligases together without requiring E3 binders, known protein binders, or binding pockets in proteins. MGDs may allow for the degradation of proteins not accessible to PROTACs and provide access to novel E3 ubiquitin ligases. Additionally, they can allow for oral delivery, broad penetration of the central nervous system, and distribution across all brain regions.8-9
- Varshavsky A. 2006 The early history of the ubiquitin field. Protein Sci. 15, 647-654. doi:10.1110/ps.052012306
- Hershko A, et al., Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proc. Natl Acad. Sci. USA 77, 1783-1786 (1980). doi:10.1073/pnas.77.4.1783
- Hershko A, Heller H, Elias S, Ciechanover A., Components of ubiquitin–protein ligase system. Resolution, affinity purification, and role in protein breakdown. J. Biol. Chem. 258, 8206-8214 (1983). doi:10.1016/S0021-9258(20)82050-X
- Hershko A, Ciechanover A, Varshvsky A. The ubiquitin system. Nat. Med. 10, 1073-1081 (2000). doi:10.1038/80384
- Sun, X., Gao, H., Yang, Y. et al. PROTACs: great opportunities for academia and industry. Sig Transduct Target Ther 4, 64 (2019). doi:10.1038/s41392-019-0101-6
- Konstantinidou M, et al. PROTACs- a game-changing technology. Expert Opin Drug Discov. 2019;14(12):1255-1268. Doi: 10.1080/17460441.2019.1659242
- Pike A, Williamson B et al., Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discov Today. 2020; 25(10):1793-1800.; Moreau K, Coen M et al. Proteolysis‐targeting chimeras in drug development: A safety perspective. J Pharmacol. 2020;177:1709–1718. doi:10.1016/j.drudis.2020.07.013
- Schreiber SL, The Rise of Molecular Glues. Cell, 2021 Jan 7;184(1):3-9. doi:10.1016/j.cell.2020.12.020
- Janet M. Sasso et al., Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Biochemistry 2023 62 (3), 601-623. doi:10.1021/acs.biochem.2c00245
- Wells, J.A., Kumru, K. Extracellular targeted protein degradation: an emerging modality for drug discovery. Nat Rev Drug Discov 23, 126–140 (2024). doi:10.1038/s41573-023-00833-z