Design, synthesis, and evaluation of PD-L1 degraders to enhance T cell killing activity against melanoma

Inhibitor targeting immune checkpoint is a promising new anticancer therapy. Blocking the interaction between PD-1 and PD-L1 can reverse the immunosuppression state and improve the lethality of immune cells to tumor cells. Here, we report PROTAC-based PD-L1 degraders to enhance T cell killing activity against melanoma. Four series of PD-L1 degraders were designed and synthesized to VHL, CRBN, MDM2 or cIAP E3 ligase system, in which CRBN-ligand-based compound BMS-37-C3 was identified as the most active PROTAC molecule. BMS-37-C3 also significantly enhanced the killing ability of T cells in a co-culture model of A375 and T cells. Furthermore, western blot data and flow cytometry demonstrated that BMS-37-C3 could reduce the protein levels of PD-L1 in dose and time dependent manner, which may provide a new therapeutic method for tumor immunotherapy. A novel PD-L1 degrader BMS-37-C3 could efficiently induce the degradation of PD-L1 in different cancer cell lines in dose-dependent and time-dependent manners. In a co-culture model of A375 and T cells, by degrading intracellular PD-L1, the direct killing effect of T cells on tumor cells was enhanced significantly. [Display omitted]