Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders

Transducin β-like protein 1 X-linked (TBL1X) is an essential scaffold protein involved in multiple signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Recent studies, however, suggest that TBL1X might modulate Wnt-regulated genes independently of β-catenin in diffuse large B-cell lymphoma (DLBCL). Here, we developed selective TBL1X degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy as a proof-of-concept. Eight PROTACs showed strong cytotoxic activity. Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation. Our mechanistic study revealed that TBL1X degradation induced by