Leveraging nature’s protein disposal system
A critical component of the body’s natural protein disposal system is a large group of proteins, called E3 ligases, that recognizes mutated and misfolded proteins, or proteins that are no longer needed, and tags them with ubiquitin protein molecules. This ubiquitin tag directs the target proteins to the proteasome, a large cellular complex that subsequently degrades the tagged protein into small peptides. PROTAC protein degraders work by recruiting a chosen E3 ligase into close proximity with a specific disease-causing protein so that it can be tagged with ubiquitin and sent off for degradation by the proteasome. After the protein is degraded, the PROTAC is released to continue its degradation mission.
PROTAC-mediated protein degradation has multiple benefits over other modalities:
- Targeting the “Undruggable” – Traditional small molecule inhibitors require strong binding to a target protein, often to its active site. Since PROTAC protein degraders only need to bind weakly to the target protein in order to specifically “tag” it, the ~80% of the proteome that is currently “undruggable” may be addressable by PROTAC degraders.
- Multiple routes of administration – We can generate PROTAC protein degraders to be delivered orally, via injection, or via infusion, depending on the disease and need.
- Crossing the blood/brain barrier – In preclinical studies, our PROTAC protein degraders have successfully penetrated the blood-brain barrier, a key step in developing drugs to treat neurodegenerative diseases.
- Potential for tissue-specific targeting – Unlike other small molecules, the activity of a PROTAC degrader can be targeted to a specific tissue by recruiting an E3 ligase which is expressed only in that cell lineage.
- Benefits of small molecules – In contrast to some other novel modalities, PROTAC protein degraders have broad distribution in the body and can be manufactured using well-understood processes.