2. Academic Validation
  3. Synthesis and immunotherapy efficacy of a PD-L1 small-molecule inhibitor combined with its 131I-iodide labelled isostructural compound

Synthesis and immunotherapy efficacy of a PD-L1 small-molecule inhibitor combined with its 131I-iodide labelled isostructural compound

  • Bioorg Chem. 2024 Sep 7:153:107810. doi: 10.1016/j.bioorg.2024.107810.
Gaochao Lv 1,  Xin Hu 1,  Nan Zhang 1,  Junyi Zhu 1,  Xiaoqing Gao 2,  Hongjie Xi 2,  Ying Peng 2,  Quan Xie 2,  Ling Qiu 3,  Jianguo Lin 4
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 2 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China.
  • 3 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China. Electronic address: qiuling@jsinm.org.
  • 4 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China. Electronic address: linjianguo@jsinm.org.
PMID: 39276489 DOI: 10.1016/j.bioorg.2024.107810
Abstract

Although antibody-based Immune Checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, LG-12, was developed and radiolabeled with 131I to obtain the chemically and biologically identical radiopharmaceutical [131I]LG-12, which aimed to improve the antitumor effect by combination of LG-12 and [131I]LG-12. LG-12 showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [131I]LG-12 could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [131I]LG-12 and LG-12 could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.

Keywords

Combination therapy; Immunotherapy; PD-L1; Small molecule; Targeted radionuclide therapy.

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