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.

The Need

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.

The Technology

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.

Commercial Applications

Therapeutic targeting degradation of pathological proteins to treat a variety of cancers

Benefits/Advantages

• Engagement with both the protein of interest (POI) and the E3 ligase simultaneously, which results in POI ubiquitination and subsequent proteasomal degradation.
• Potent TBL1 degradation activity, DLBCL cytotoxicity and good metabolic stability and PK/PD properties.

Patents

• Provisional application filed