Transducin β-like protein 1 (TBL1) is an essential scaffold protein that participates in multiple critical signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Only one compound, BC-2059 (tegavivint, Iterion Therapeutics), has been reported to promote apoptosis by disrupting the TBL1/β-catenin interactions and show promising therapeutic effects in Wnt-driven cancers, such as colorectal cancer, breast cancer, and leukemia. However, recent studies showed that TBL1 modulates Wnt-regulated genes in a β-catenin-independent manner in diffuse large B-cell lymphoma (DLBCL). Although the involvement of β-catenin is still under debate, TBL1’s engagement in the antitumor effects of BC-2059 is certain and critical. In this study, we aimed to develop proof-of-concept BC-2059-based TBL1 selective degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy and use them as chemical probes to investigate TBL1-related pathways in DLBCL. Two series (N- and O-linked) of BC-2059-based PROTACs were synthesized, and their cytotoxicity and protein degradation profiles were tested in cellular assays. Several compounds showed moderate cytotoxic activity. We modeled the ternary complex formation by developing a workflow where two binary complexes and a library of PROTACs having varied linker lengths/chemical compositions were modeled by PRosettaC. The protein-protein interactions of the generated ternary complexes were analyzed by Rosetta and the interactions between the linkers and the protein were calculated by Autodock 4. The results suggested that short linkers (8-14 heavy atoms) are more suitable for N-linked series degraders in terms of PROTAC-induced ternary complex formation, while long linkers (&gt;18 heavy atoms) are preferable for O-linked series.

Design, synthesis, and biological evaluation of TBL1 degraders

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