The vast majority of newly developed PROTACs currently in clinical trials target a variety of cancers. However, given their potential to degrade undruggable targets, the scope of PROTAC is expanding beyond oncology. With the development of PROTAC technology, this innovative therapeutic approach shows its potential in autoimmune disease treatment. Two PROTAC compounds already in phase I clinical trials that could test PROTAC modality in non-oncology indications are KT-474, and NX-5948, targeting BTK and IRAK4, respectively, both in Phase I clinical trials for the treatment of various immunoinflammatory diseases, such as rheumatoid arthritis.
In academia, there are many PROTACs have been developed for autoimmune diseases. For example, a series of PROTAC molecules targeting IRAK4 have been reported. Molecular docking studies based on the crystal structures of IRAK4 and its kinase inhibitor complexes successfully predicted the optimal location for binding IRAK4 ligands. Finally, multiple IRAK4 PROTAC molecules were generated by assembling E3 ligands, linker, and IRAK4 ligands.
