2. Academic Validation
  3. In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)

In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)

  • Bioorg Chem. 2021 Jun;111:104833. doi: 10.1016/j.bioorg.2021.104833.
Yubo Wang 1,  Yuanyuan Zhou 1,  Sheng Cao 1,  Yue Sun 1,  Zhiqiang Dong 1,  Chen Li 1,  Haoran Wang 1,  Yuhong Yao 1,  Haiyan Yu 2,  Xiangyi Song 2,  Ming Li 3,  Jiefu Wang 4,  Mingming Wei 5,  Guang Yang 6,  Cheng Yang 1
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
  • 2 Tianjin Pacific Chemical & Pharmaceutical Co., LTD, Tianjin 300350, PR China.
  • 3 Cangzhou Institutes for Food and Drug Control, Cangzhou 061000, PR China.
  • 4 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, PR China. Electronic address: [email protected].
  • 5 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: [email protected].
  • 6 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: [email protected].
PMID: 33839580 DOI: 10.1016/j.bioorg.2021.104833
Abstract

Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing Antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 Cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for Cancer Immunotherapy.

Keywords

BMS-37 derivatives; Immunotherapy; PD-L1; PROTACs.

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