Problem

Transducin β-like protein 1 (TBL1) has emerged as a promising therapeutic target in oncology, due to its central role in regulating multiple oncogenic signaling pathways. The challenge is how to develop a selective and effective inhibitor of TBL1 with high efficacy and limited side-effects

Solution

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. The degrader molecules demonstrated significant cytotoxicity and potent TBL1X degradation in DLBCL cells with IC50 in nM range.

Application

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

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, and cytotoxicity with IC50 in nM range

Seeking opportunities for out-licensing and collaboration