PD-L1/SHP2 dual PROTACs inhibit melanoma by enhancing T-cell killing activity

Abstract

Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1) protein-protein interaction represents an appealing target for cancer therapy. Several antibody drugs have been developed to target this interaction, but they are less effective in the treatment of melanoma. To overcome the limitations, the first proteolysis-targeting chimeric (PROTAC) small molecules simultaneously targeting PD-L1 and Src homology phosphotyrosyl phosphatase 2 (SHP2) were designed. By employment of PD-1/PD-L1 inhibitors BMS01 or BMS-37, SHP2 inhibitor SHP099 and E3 ligase ligands, a series of potent PD-L1 and SHP2 dual PROTACs were synthesized. The most promising compounds BS-7C-V2 and BS327V2 efficiently induced PD-L1 and SHP2 degradation and demonstrated significantly improved immune potency in B16-F10 and A375 cell lines. More importantly, the efficacy of BS-7C-V2 and BS327V2 in a B16-F10 transplanted mouse model was further evaluated based on their degradation ability in vivo. Taken together, our work qualifies the new dual PROTACs as a potent degrader of PD-L1 and SHP2. The biological and mechanism investigations with BS-7C-V2 and BS327V2 prove that dual PROTACs can play an anti-tumor role in vivo and in vitro, and can provide a new therapeutic strategy for melanoma.