Citation: Yang Liu, Mengzhu Zheng, Zhilu Ma, Yirong Zhou, Junfeng Huo, Wenbo Zhang, Yu Liu, Yuanyuan Guo, Xuechen Zhou, Hua Li, Lixia Chen. Design, synthesis, and evaluation of PD-L1 degraders to enhance T cell killing activity against melanoma[J]. Chinese Chemical Letters, ;2023, 34(5): 107762. doi: 10.1016/j.cclet.2022.107762 shu

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

Yang Liu ^{a, 1} ,
Mengzhu Zheng ^{c, 1} ,
Zhilu Ma ^{c, 1} ,
Yirong Zhou ^c ,
Junfeng Huo ^c ,
Wenbo Zhang ^a ,
Yu Liu ^c ,
Yuanyuan Guo ^a ,
Xuechen Zhou ^c ,
Hua Li ^{a, b, c, *,} ,
Lixia Chen ^{a, *,}

a.
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
b.
College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
c.
School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

li_hua@hust.edu.cn

syzyclx@163.com

Received Date: 11 June 2022
Revised Date: 16 August 2022
Accepted Date: 17 August 2022
Available Online: 20 August 2022

Figures(5)

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.
- PD-L1,
- PROTACs,
- BMS-37-C3,
- Immunotherapy,
- Melanoma
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