Unnatural amino acid-based miniPROTACs enable efficient oncoprotein degradation

Proteolysis-targeting chimeras (PROTACs) harness the cell's proteolytic systems to eliminate harmful proteins for therapeutic purposes. Unnatural amino acids (UAAs) offer unique structural features for drug design but have not yet been applied to targeted protein degradation. Here, we develop a set of linker-free PROTACs in which Lys-derived UAAs-ornithine (Orn) and 2,4-diaminobutyric acid (Dab)-serve as degrons that are directly conjugated to target ligands, yielding compact and effective degraders. Both Orn-BA and Dab-BA promote the efficient degradation of EML4-ALK, with Dab-BA exhibiting superior potency, attributed to its enhanced ability to promote ternary complex formation with the target and E3 ligase. Dab-BA also significantly suppresses tumor growth in a xenograft mouse model. The general applicability of this UAA-based linker-free PROTAC approach is further demonstrated by the development of BCR-ABL degraders. Our study represents the first application of UAAs in targeted protein degradation and offers a complementary strategy for E3 ligand discovery.