2. Academic Validation
  3. Discovery of 1,3,4-oxadiazole derivatives as potential antitumor agents inhibiting the programmed cell death-1/programmed cell death-ligand 1 interaction

Discovery of 1,3,4-oxadiazole derivatives as potential antitumor agents inhibiting the programmed cell death-1/programmed cell death-ligand 1 interaction

  • Bioorg Med Chem. 2021 Sep 15;46:116370. doi: 10.1016/j.bmc.2021.116370.
Lincheng Fang 1,  Jiping Tian 1,  Kaixuan Zhang 1,  Xiaoyi Zhang 1,  Yingqiao Liu 2,  Zhibo Cheng 3,  Jinpei Zhou 4,  Huibin Zhang 5
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
  • 2 College of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.
  • 5 Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zhanghb80@163.com.
PMID: 34481337 DOI: 10.1016/j.bmc.2021.116370
Abstract

Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by small-molecule inhibitors is emerging Cancer Immunotherapy. A series of novel 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for their activities in vitro and vivo to find potent inhibitors of the PD-1/PD-L1 interaction. Among them, compoundⅡ-14exhibited outstanding biochemical activity, with an IC50of 0.0380 μM. Importantly, compound II-14, with a TGI value of 35.74 %, had more potent efficacy in a mouse tumor model compared to that in the control group. Surprisingly, when compound II-14 combined with 5-FU in a mouse tumor model having a TGI value of 64.59 %, which showed potential anti-tumor synergistic effects. Furthermore, immunohistochemistry analysis demonstrated thatcompound II-14 activated the immune microenvironment by promoting the infiltration of CD4+ T cells into tumor tissues. These results indicate that compound II-14 is a promising lead compound for further development of small-molecule PD-1/PD-L1 inhibitors for Cancer therapy.

Keywords

Molecular docking; PD-1/PD-L1; Small molecule inhibitor; Tumor immunity.

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