Our research has revealed that lymphoid malignancies depend on GSK3B-mediated degradation of beta-catenin. While existing GSK3A/GSK3B dual inhibitors have shown favorable safety in clinical trials, they require continuous intravenous infusion and affect multiple cell types.

We found that selective inhibition of GSK3B alone is sufficient to trigger beta-catenin accumulation and cell death in lymphoid malignancies, without impacting other cell types that require dual inhibition of GSK3A and GSK3B. To achieve this selectivity, we have designed compounds that exploit a single amino acid difference in the ATP-binding domain of the two kinases.

Using our proprietary high-throughput screening assay and Yale’s collection of 460,000 small molecules, we have identified lead compounds optimized for GSK3B selectivity and oral bioavailability, now protected under US patent 63/346,407.