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基于吲哚的磷脂酶D抑制剂用于肺癌免疫治疗的研发与评估

Development and Evaluation of Indole-Based Phospholipase D Inhibitors for Lung Cancer Immunotherapy.

作者信息

Song Doona, Lim Seong Hun, Kim Yeji, Lee Hyesung, Kim Taehyun, Lim Hocheol, Min Do Sik, Han Gyoonhee

机构信息

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.

Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.

出版信息

J Med Chem. 2025 Mar 13;68(5):5170-5189. doi: 10.1021/acs.jmedchem.4c00750. Epub 2024 Oct 15.

DOI:10.1021/acs.jmedchem.4c00750
PMID:39405365
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11913021/
Abstract

This study explored novel immunomodulatory approaches for cancer treatment, with a specific focus on lung cancer, the leading cause of cancer-related deaths worldwide. We synthesized indole-based phospholipase D (PLD) inhibitors with various substituents to improve anticancer efficacy. Through structure-activity relationship studies, the key compound was identified that significantly inhibiting PLD, suppressing cell growth, viability, and migration while inducing apoptosis of lung cancer cells. docking studies confirmed its binding to the PLD1 active site, highlighting the role of specific residues in inhibiting PLD1 activity. The inhibitor modulated oncogenic pathways and immune evasion in lung cancer cells, showing potential for immunotherapy. experiments in a mouse model showed tumor reduction and immune response alteration. Combining these inhibitors with gemcitabine, an anticancer drug, synergistically enhanced inhibition of lung cancer cell apoptosis and proliferation. This research offers new insights into PLD inhibitor as potential cancer therapeutics.

摘要

本研究探索了用于癌症治疗的新型免疫调节方法，特别关注肺癌，肺癌是全球癌症相关死亡的主要原因。我们合成了具有各种取代基的吲哚基磷脂酶D（PLD）抑制剂，以提高抗癌疗效。通过构效关系研究，确定了关键化合物，该化合物可显著抑制PLD，抑制细胞生长、活力和迁移，同时诱导肺癌细胞凋亡。对接研究证实了其与PLD1活性位点的结合，突出了特定残基在抑制PLD1活性中的作用。该抑制剂调节肺癌细胞中的致癌途径和免疫逃逸，显示出免疫治疗的潜力。在小鼠模型中的实验表明肿瘤缩小和免疫反应改变。将这些抑制剂与抗癌药物吉西他滨联合使用，可协同增强对肺癌细胞凋亡和增殖的抑制作用。这项研究为PLD抑制剂作为潜在的癌症治疗药物提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/821c11faad85/jm4c00750_0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/821c11faad85/jm4c00750_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/26145db2f12d/jm4c00750_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/4154c27c66ce/jm4c00750_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/c86a6a0b8a35/jm4c00750_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/169d7cfed6e9/jm4c00750_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/98e51150fb57/jm4c00750_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/30f5a5c32509/jm4c00750_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/a23209d75fef/jm4c00750_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/b8cf369a1560/jm4c00750_0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9ae/11913021/821c11faad85/jm4c00750_0009.jpg

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本文引用的文献

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RBM10 Loss Promotes EGFR-Driven Lung Cancer and Confers Sensitivity to Spliceosome Inhibition.RBM10 缺失促进 EGFR 驱动的肺癌发生，并对剪接体抑制敏感。
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Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47.
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