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创新性的PDK1降解PROTACs改变乳腺癌有氧糖酵解并诱导免疫原性细胞死亡

Innovative PDK1-Degrading PROTACs Transform Cancer Aerobic Glycolysis and Induce Immunogenic Cell Death in Breast Cancer.

作者信息

Deng Aohua, Fan Renming, Gou Jiakui, Sang Ruoxi, Lin Ruizhuo, Zhao Ting, Zhuang Junyan, Hai Yongrui, Sun Jialin, Wei Gaofei

机构信息

Institute of Medical Research Northwestern Polytechnical University Xi'an Shaanxi China.

Research & Development Institute of Northwestern Polytechnical University in Shenzhen Guangdong China.

出版信息

Exploration (Beijing). 2025 May 7;5(4):e20240031. doi: 10.1002/EXP.20240031. eCollection 2025 Aug.

DOI:10.1002/EXP.20240031
PMID:40873633
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12380065/
Abstract

Cancer cells are characterized by the Warburg effect, which hijacks glycolysis and hinders OXPHOS. Pyruvate dehydrogenase kinase 1 (PDK1) is a key modulator in the Warburg effect and is highly expressed in tumor cells. We utilize PROTAC technology to design compounds that could achieve long-lasting degradation on PDK1. After screening anti-tumor activity in vitro, we selected a top compound , among 22 chemical candidates in various structures. Compared to a conventional PDK1 inhibitor, dramatically improves over 1000-fold proliferation inhibition efficacy. Besides, reverses Warburg effect and causes tumor apoptosis. In vivo, achieves potent therapeutic efficacy in tumor-bearing mice and dramatically prolongs their lifetime after surgery resection. For the mechanism, induces immunogenic cell death and reverses immunosuppression in the TME to enhance antitumor immunoreactivity. Further, transcriptome analysis verifies the mechanisms and uncovers fluctuation in cancer related pathways. Combination with αPD-L1 improves therapeutic efficacy and promotes multiple immunocytes infiltration. In conclusion, we first utilize PROTAC technology on modulating aberrant expressed metabolic enzyme PDK1 in cancer cells and achieve a great pharmacological effect, rendering it promising for energy-aberrant cancer therapy.

摘要

癌细胞具有瓦伯格效应的特征，该效应劫持糖酵解并阻碍氧化磷酸化。丙酮酸脱氢酶激酶1（PDK1）是瓦伯格效应中的关键调节因子，在肿瘤细胞中高度表达。我们利用PROTAC技术设计能够实现对PDK1持久降解的化合物。在体外筛选抗肿瘤活性后，我们从22种不同结构的化学候选物中选择了一种顶级化合物。与传统的PDK1抑制剂相比，其增殖抑制功效显著提高了1000倍以上。此外，它能逆转瓦伯格效应并导致肿瘤细胞凋亡。在体内，它在荷瘤小鼠中实现了强效治疗效果，并在手术切除后显著延长了它们的生存期。就机制而言，它诱导免疫原性细胞死亡并逆转肿瘤微环境中的免疫抑制以增强抗肿瘤免疫反应。此外，转录组分析验证了这些机制并揭示了癌症相关途径的波动。与αPD-L1联合使用可提高治疗效果并促进多种免疫细胞浸润。总之，我们首次利用PROTAC技术调节癌细胞中异常表达的代谢酶PDK1，并取得了显著的药理效果，使其在能量异常的癌症治疗中具有前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fdc/12380065/4db612488cae/EXP2-5-e20240031-g021.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fdc/12380065/4db612488cae/EXP2-5-e20240031-g021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fdc/12380065/d0ab9bf256c7/EXP2-5-e20240031-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fdc/12380065/0adff329ebc5/EXP2-5-e20240031-g029.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fdc/12380065/8f6b266dee9b/EXP2-5-e20240031-g028.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fdc/12380065/4db612488cae/EXP2-5-e20240031-g021.jpg

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本文引用的文献

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Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy.己糖激酶 2 的降解阻断糖酵解并诱导 GSDME 依赖性细胞焦亡以增强乳腺癌治疗的免疫原性细胞死亡。
J Med Chem. 2023 Jul 13;66(13):8464-8483. doi: 10.1021/acs.jmedchem.3c00118. Epub 2023 Jun 27.
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Harnessing the cyclization strategy for new drug discovery.利用环化策略进行新药研发。
Acta Pharm Sin B. 2022 Dec;12(12):4309-4326. doi: 10.1016/j.apsb.2022.09.022. Epub 2022 Oct 7.
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Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression.
基于肽的 FOXM1 PROTAC 降解剂抑制癌症并降低 GLUT1 和 PD-L1 的表达。
J Exp Clin Cancer Res. 2022 Sep 29;41(1):289. doi: 10.1186/s13046-022-02483-2.
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A mitochondria targeted cascade reaction nanosystem for improved therapeutic effect by overcoming cellular resistance.一种线粒体靶向级联反应纳米系统，通过克服细胞耐药性来提高治疗效果。
Biomater Sci. 2022 Oct 11;10(20):5947-5955. doi: 10.1039/d2bm00956k.
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Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope.非小分子PROTAC（NSM-PROTAC）：蛋白质降解万花筒
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NAMPT-targeting PROTAC promotes antitumor immunity suppressing myeloid-derived suppressor cell expansion.靶向烟酰胺磷酸核糖转移酶（NAMPT）的蛋白水解靶向嵌合体（PROTAC）通过抑制髓源性抑制细胞的扩增来促进抗肿瘤免疫。
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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021).PROTACs：学术和工业界的巨大机遇（2020 年至 2021 年更新）。
Signal Transduct Target Ther. 2022 Jun 9;7(1):181. doi: 10.1038/s41392-022-00999-9.
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A Sub-6 nm MnFeO-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy.一种亚 6 纳米 MnFeO-二氯乙酸纳米复合材料调节肿瘤代谢和分解代谢，逆转肿瘤免疫抑制微环境，增强免疫治疗。
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