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

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-09-07 DOI:10.1016/j.bioorg.2024.107810

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引用次数: 0

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.

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一种 PD-L1 小分子抑制剂与其 131I-iodide 标记的同结构化合物的合成及其免疫治疗功效

虽然基于抗体的免疫检查点阻断剂已成功应用于抗肿瘤免疫疗法，但反应率低是目前的主要问题。本研究开发了一种小分子程序性细胞死亡配体（PD-L1）抑制剂LG-12，并用131I进行放射性标记，得到了化学和生物学相同的放射性药物[131I]LG-12，旨在通过LG-12和[131I]LG-12的联合使用提高抗肿瘤效果。LG-12对PD-1/PD-L1的相互作用具有很高的抑制活性。细胞摄取和生物分布研究结果表明，[131I]LG-12能与B16-F10肿瘤中的PD-L1特异性结合。它能诱导免疫性细胞死亡，并释放高迁移率基团框 1 和钙网蛋白。[131I]LG-12和LG-12联合使用可显著抑制肿瘤生长，并增强抗肿瘤免疫反应。这种基于PD-L1小分子抑制剂的联合策略在肿瘤治疗中具有巨大潜力。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.