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 im-mune cells to tumor cells. Here, we report PROTAC-based PD-L1 degraders to enhance T cell killing ac-tivity 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.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

Inhibitors targeting immune checkpoint provide a promising anticancer therapy by reversing immunosuppression and enhancing immune cell lethality to tumor cells. This study reports the development of PROTAC-based PD-L1 degraders that improve T cell killing activity against melanoma. Among the designed degraders, CRBN-ligand-based compound BMS-37-C3 shows the most potent activity in degrading PD-L1 and enhancing T cell killing ability.