Targeted Protein Degradation
Previously over 1,500 proteins reported as being pathogenic or potentially related to certain diseases and 90% of them are thought as “undruggable” for targeted drug development with small molecules or monoclonal antibodies to inhibit or modulate the function. Targeted protein degradation approach is an emerging strategy to access those undruggable targets and has huge potential in drug development.
Protein degraders are bi-functional molecules and work to recruit a protein of interest to E3 ligase. By hijacking ubiquitin-proteasome system in the cells, the protein of interest can be degraded. Protein degraders are released after protein degradation to continue further protein degradation.
Discovery Platform – RaPPIDSTM
RaPPIDSTM is a powerful platform for protein degrader development based on diversity-oriented synthesis (DOS) approach.
In the first step of RaPPIDSTM, 20 to 50 protein degraders are quickly generated using “ready-to-conjugate probe library” to assess potential E3 ligase binder and linker length. Selection of E3 ligase is the key for successful protein degrader discovery but options of E3 ligase for protein degrader are still limited. We can generate protein degraders based on original XIAP binders, not only VHL and CRBN, and the discovery of new E3 ligase binders is invested to expand the capability of protein degrader development.
Second step of RaPPIDSTM is high-throughput semi-automated DOS and lead optimization phase. We strongly believe that DOS approach is the best way to identify the best degrader because precise in silico design or prediction is difficult even if we have structural information of protein of interest and targeted E3 ligase.