Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy.

The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor and the E3 ligand as foundational components. Among these, we identified a highly potent molecule for PD-L1 degradation in 4T1 cells (DC = 0.609 μM). Significantly, compound potentially inhibits 4T1 cell growth both and . Further mechanistic studies revealed that effectively promoted the immune activation of model mice. Thus, these results suggest that could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.