PROTACs as Next Generation Bcl3 inhibitors – Chemical Tools to Induce Selective Protein Degradation

There is an urgent unmet medical need for better treatments for patients suffering from advanced colorectal (bowel) cancer, especially those patients carrying a mutation in a key cellular controller protein known as KRas (representing around 40% of patients). KRas mutant bowel cancer patients lack effective treatments, with <50% surviving beyond 5 years. Recently, our team have identified a new drug candidate to target Bcl3, a protein identified by the Cardiff team that drives fundamental features of bowel cancer (e.g. proliferation; invasion & metastasis). This pioneering work has led to a novel Bcl3 inhibitor drug candidate in advanced preclinical development, with a ‘clean’ safety profile for daily oral administration alongside other cancer drugs.

Given the complexities and uncertainties associated with cancer drug development, we need alternative therapeutic approaches. In this context, an emerging technology for selective protein degradation known as PROteolysis Targeting Chimeras (PROTACs) is an attractive approach. Although some PROTACs have progressed to clinical evaluation, none target Bcl3. 

We will synthesise Cardiff Bcl3 inhibitors chemically linked to molecules that engage selective protein destruction. Selective degradation of the Bcl3 protein in cancer cells will be assessed, and the most promising new PROTAC drug candidate will be progressed for future patient benefit.