Discovery of small molecule 13-catenin suppressors that enhance immunotherapy

Small molecules directly downregulating 13-catenin could potentially offer a more effective therapeutic approach for combating against cancer stem cells, as compared to targeting the downstream components of the Wnt/ 13-catenin pathway. The challenge, however, lies in the fact that very few 13-catenin suppressors have proven clinically effective, leaving a significant gap in medical solutions. Given that E-cadherin has a natural affinity for 13-catenin, it stands to reason that agents designed to increase E-cadherin expression might provide an alternative method of regulating 13-catenin levels. In this study, we report our discovery of DSS-C12 and DSS-B8, specific ester-based drugs derived from Dan-Shen-Su (DSS) extracted from the herb Salvia miltiorrhiza. Remarkably, these compounds display a potent ability to downregulate 13-catenin, while also improving overall survival in post surgery mice. Additionally, when these drugs are used in combination with PD-L1 checkpoint blockade, they stimulate enhanced systemic immune responses leading to significant suppression of primary tumor growth. Indepth mechanistic studies revealed that DSS-B8 functions as a vitamin D receptor agonist without inducing hypercalcemic effects. Collectively, our findings indicate that DSS-derived small molecules have considerable potential as clinically viable therapeutic strategies for 13-catenin deactivation.

Automated summary

Small molecules directly downregulating β-catenin have the potential to be more effective in combating cancer stem cells compared to targeting downstream components of the Wnt/β-catenin pathway. However, clinically effective β-catenin suppressors are lacking, creating a significant gap in medical solutions. In this study, we discovered DSS-C12 and DSS-B8, ester-based drugs derived from DSS, which effectively downregulate β-catenin and improve overall survival in post-surgery mice. Furthermore, combining these drugs with PD-L1 checkpoint blockade stimulates enhanced systemic immune responses and suppresses primary tumor growth.