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  2. Discovery of quinazoline derivatives as novel small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction

Discovery of quinazoline derivatives as novel small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction

  • Eur J Med Chem. 2022 Feb 5;229:113998. doi: 10.1016/j.ejmech.2021.113998.
Yu Wang 1 Kun Huang 1 Yali Gao 2 Dandan Yuan 1 Lin Ling 3 Jieqing Liu 1 Sihai Wu 1 Roufen Chen 1 He Li 1 Yizu Xiong 1 Han Liu 1 Junjie Ma 4
Affiliations

Affiliations

  • 1 School of Medicine, Huaqiao University, Quanzhou, 362000, China.
  • 2 Pharmacy Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China.
  • 3 Quanzhou First Hospital, Fujian Medical University, Fuzhou, 350108, China.
  • 4 School of Medicine, Huaqiao University, Quanzhou, 362000, China. Electronic address: majunjie3612@hqu.edu.cn.
Abstract

Development of small molecule PD-1/PD-L1 inhibitors as a novel immunotherapy strategy exhibits great promise. Herein, a novel series of quinazoline derivatives were designed, synthesized and their inhibitory activity against the PD-1/PD-L1 interaction was evaluated through a homogenous time-resolved fluorescence (HTRF) assay. Among them, the compound 39 exhibited the most potent inhibitory activity with an IC50 value of 1.57 nM. Furthermore, the cellular level assays revealed that 39 could inhibit the PD-1/PD-L1 interaction and restore T-cell function, and showed low toxicity on the PBMCs. In addition, the structure-activity relationships (SARs) of the novel quinazoline derivatives were explored and the binding mode of 39 with dimeric PD-L1 was analyzed by molecular docking. This work demonstrates that incorporation of pyrimidine group between the 2 and 3-positions of the biphenyl structure is an effective strategy for designing novel and more potent small molecule PD-1/PD-L1 inhibitors, and 39 can be regarded as a promising lead compound for further investigation.

Keywords

PD-1/PD-L1 interaction; Quinazoline derivatives; Small molecule inhibitors; Tumor immunotherapy.

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