KCS

Protein-protein interaction (PPI) plays a pivotal role in various biological systems and many complex diseases including cancer, neurodegenerative diseases, and metabolic diseases are often caused by aberrant PPIs. Given its significance in the biological systems, the identification of PPI modulators could be a starting point for drug discovery and chemical biology research. However, the high-throughput screening of conventional compound libraries hasn’t been successful, due to the different structural requirement of PPI modulators. Thus, there is a great demand in the construction of novel molecular diversity. Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. Modulating target proteins via the ubiquitin-proteasome system has recently broadened the scope of pharmacological inventions. Stimulator of interferon genes (STING) activation is a promising strategy for immuno-oncology that promotes systemic antitumor immunity at the interface of innate and adaptive immunity. However, from the current clinical investigations of STING agonists, dysregulated STING expression or poor STING agonist pharmacokinetics pose major challenges that limit the robust antitumor response. Herein, we propose UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to overcome these limitations. We discovered that the small molecule SB24011 inhibits the STING–TRIM29 E3 ligase interaction, thereby blocking the TRIM29-mediated STING degradation. SB24011 enhanced the cGAMP-mediated immunity by upregulating cellular STING levels through blocking TRIM29-induced K48 linkage-specific ubiquitination. Thus, SB24011 potentiated the immuno-oncological efficacy of cGAMP and anti-PD-1 therapy for tumor regression, confirmed in CT26 and B16F10 syngeneic mouse models. Our work successfully demonstrated that targeted protein upregulation of STING is a promising strategy for cancer immunotherapy. Furthermore, UPPRIS could be utilized to comprehend the unexplored protein-protein interaction interfaces and advance our understanding of biological processes. Overall, we anticipate that UPPRIS, an opposite approach of PROTAC, brings breakthroughs in clinical and academic research fields.