Transducin β-like protein 1 X-Linked Selective Degraders as Anti-cancer Therapeutics
Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, or nearly one in six deaths. The most common cancers are breast, lung, colon and rectum and prostate cancers.
Current cancer treatments mainly rely on chemotherapy, radiation, surgery and bone marrow transplantation. However, these can be associated with severe side effects, and in some cases the cancer does not respond to the treatments. Thus, there is an urgent need for new therapeutics that are safe and effective.
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 have shown that TBL1 modulates Wnt-regulated genes in a β-catenin-independent manner in diffuse large B-cell lymphoma (DLBCL). OSU researchers have developed BC-2059-based TBL1 selective degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy and used the degraders as anti-cancer therapeutics.
Therapeutic targeting degradation of pathological proteins to treat a variety of cancers