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CJ 2 : A Novel Potent Platinum(IV) Prodrug Enhances Chemo-Immunotherapy by Facilitating PD-L1 Degradation in the Cytoplasm and Cytomembrane.

Renming FanAohua DengBing QiShuo ZhangRuoxi SangLanxin LuoJiakui GouYongqing LiuRuizhuo LinMinggao ZhaoYang LiuLe YangMao-Sheng ChengGaofei Wei
Published in: Journal of medicinal chemistry (2023)
Platinum drugs as primary chemotherapy drugs have been applied to various cancer patients. However, their therapeutic applicability is limited due to the adverse effects and immunosuppression. To minimize the side effects and boost the immune response, we designed and synthesized platinum(IV) prodrugs that introduced BRD4 inhibitor JQ-1. Among them, CJ 2 had the most potent therapeutic activity and less toxicity. With the introduction of ligand JQ-1, CJ 2 -reduced PD-L1 protein was found in the cytoplasm and cytomembrane for the first time. By interfering with the PD-L1 synthesis, CJ 2 could arouse the immune system and promote CD8 + T cell infiltration. Meanwhile, CJ 2 could accelerate PD-L1 degradation in the cytoplasm to block DNA damage repair. In vivo, CJ 2 markedly suppressed tumor growth by reversing the immunosuppression microenvironment and enhancing DNA damage. These findings provide an effective approach to improve the selectivity and activity of the platinum drugs with elevated immune response.
Keyphrases
  • dna damage
  • immune response
  • oxidative stress
  • dna repair
  • stem cells
  • cancer therapy
  • dendritic cells
  • locally advanced
  • photodynamic therapy
  • toll like receptor
  • drug induced
  • protein protein