Expanding Therapeutic Possibilities Outside the Cell
Targeted Protein Degradation Expands the Reach of Precision Medicine
Traditional drug discovery has primarily focused on identifying a disease-causing protein and then developing a therapy that regulates its activity, particularly through inhibition. However, of the more than 4,000 disease-associated proteins that have been identified to date, only about 400 proteins have been successfully targeted with current therapies. In recent years, scientific advancements have expanded the addressable protein universe by employing a new approach: targeted degradation and elimination of disease-causing proteins, rather than just inhibition. There is significant potential for targeted protein degradation as a therapeutic approach to bridge the gap of what protein inhibition has been unable to accomplish.
Our LYTAC Platform
Based on the transformational work of Nobel laureate Dr. Carolyn Bertozzi at Stanford University, our LYTAC platform is designed to produce protein-degrading therapeutics that target extracellular proteins and shuttle them from outside the cell into the lysosome, where they are degraded. Lysosomes are naturally responsible for the degradation of some classes of extracellular proteins via endocytosis (a process by which cells internalize extracellular substances). Building on Dr. Bertozzi’s work as the foundation, we have refined and expanded the LYTAC platform to serve as our drug discovery engine.
A LYTAC (Lysosomal Targeting Chimera) degrader consists of two parts: one that binds to a target protein and another that binds to an internalizing receptor (IR) that acts as a lysosome shuttle. Together, the parts allow the LYTAC degrader to target a specific protein and internalize it through endocytosis to access the lysosomal machinery.
Learn more about the Target Binder and Internalizing Receptor »
The target binder of the LYTAC degrader is responsible for selectively binding to the target protein. It can be a small molecule, peptide, protein or antibody, and does not need to actively inhibit the target since the LYTAC degrader only requires a handle to recruit the protein to the cell for degradation. This distinction allows LYTAC degraders to access a broader set of disease-causing proteins, including those that may be difficult to modulate through conventional inhibitory approaches, focusing on what will most effectively bind the target and limit off-target interactions.
The second part of the LYTAC degrader is the internalizing receptor binder. Selecting the internalizing receptor is critical to the LYTAC degrader’s design. Internalizing receptors vary in their tissue expression and how they traffic to and from the cell surface, and therefore not every internalizing receptor is suitable for every target. Our LYTAC platform can accommodate a wide range of internalizing receptors, allowing us to promote the degradation of diverse protein classes. To date, we have designed LYTAC degraders that bind internalizing receptors for both broad-based and tissue-specific targeting. As part of our LYTAC platform, we have established a library of proprietary small and large molecule binders to multiple internalizing receptors, providing significant flexibility in the design of future LYTAC degraders in terms of targets and potential indications.
Classic LYTAC Degraders
Classic LYTAC degraders shuttle target proteins to the lysosome, where both the target and the classic LYTAC degrader are broken down.
Because classic LYTAC degraders are designed to degrade the target protein generally in a 1:1 ratio, they are well-suited for targets that have low concentrations, slow resynthesis rates or where intermittent depletion is preferred.
CataLYTACTM Degraders
Similar to classic LYTAC degraders, cataLYTAC degraders first form a ternary complex consisting of the cataLYTAC degrader, target protein and internalizing receptor, but they are unique in that they are engineered to release the ternary complex within the endosome, thereby allowing both the cataLYTAC degrader and the internalizing receptor to shuttle back to the cell surface while the target protein is degraded within the lysosome. By repeatedly cycling into and out of a cell, cataLYTAC degraders enable the degradation of multiple copies of a pathogenic protein for each cataLYTAC degrader.
CataLYTAC degraders are expected to be particularly effective for target proteins that are present in high concentrations or have a fast resynthesis rate, as they can provide an extended duration of action relative to classic LYTAC degraders.
A Sustainable Discovery Engine
Because both classic LYTAC degraders and cataLYTAC degraders share a common two-part design, our library of proprietary internalizing receptor binders can be redeployed across programs and combined with new target binders to generate degraders against additional disease-causing proteins. By selecting a promising modality and category of LYTAC degrader, we can develop a highly customizable therapeutic designed to selectively target the protein of interest. We believe the flexibility of our LYTAC platform serves as a sustainable research and development engine that provides broad opportunities to expand our pipeline.
