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 ce...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 c IAP 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.展开更多
基金supported by the National Natural Science Foundation of China(NSFC,Nos.82141216,81773637 and 81903863)the National Mega-project for Innovative Drugs(No.2019ZX09721001-004-007,China)+2 种基金the Chunhui Program-Cooperative Research Project of the Ministry of Education,the Natural Science Foundation of Hubei Province(No.2020CFB642)the Liaoning Province Natural Science Foundation(No.2020-MZLH-31)Shenyang Young and Middle-aged Innovative Talents Support Program(No.RC210446)。
文摘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 c IAP 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.
