<br>一种新型 AMPK 抑制剂使胰腺癌细胞对铁死亡诱导敏感,Advanced Science

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一种新型 AMPK 抑制剂使胰腺癌细胞对铁死亡诱导敏感
Advanced Science ( IF 14.3 ) Pub Date : 2024-06-17 , DOI: 10.1002/advs.202307695
Carolin Schneider ₁ , Jorina Hilbert ₁ , Franziska Genevaux ₂ , Stefanie Höfer ₃ , Lukas Krauß ₁ , Felix Schicktanz ₄ , Constanza Tapia Contreras ₁ , Shaishavi Jansari ₅ , Aristeidis Papargyriou _{2,

6,

7,

8} , Thorsten Richter ₁ , Abdallah M Alfayomy _{9,

10} , Chiara Falcomatà _{11,

12} , Christian Schneeweis ₁₁ , Felix Orben ₂ , Ruppert Öllinger ₁₃ , Florian Wegwitz ₅ , Angela Boshnakovska ₁₄ , Peter Rehling _{14,

15} , Denise Müller ₁₆ , Philipp Ströbel _{16,

17,

18} , Volker Ellenrieder _{17,

18,

19} , Lena Conradi _{1,

17,

18} , Elisabeth Hessmann _{17,

18,

19} , Michael Ghadimi _{1,

18} , Marian Grade _{1,

18} , Matthias Wirth _{1,

20} , Katja Steiger _{4,

21} , Roland Rad _{13,

21} , Bernhard Kuster _{3,

21} , Wolfgang Sippl ₉ , Maximilian Reichert _{2,

7,

8,

21,

22} , Dieter Saur _{11,

21} , Günter Schneider _{1,

11,

17,

18}

Affiliation

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
Proteomics and Bioanalytics, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, 85354, Freising, Germany.
Institute of Pathology, Technical University of Munich, 81675, Munich, Germany.
Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
Institute of Stem Cell Research, Helmholtz Zentrum Muenchen, D-85764, Neuherberg, Germany.
Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
Center for Organoid Systems (COS), Technical University of Munich, 85747, Garching, Germany.
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany.
Department of Pharmaceutical Chemistry, Al-Azhar University, Assiut, 71524, Egypt.
Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, 81675, Munich, Germany.
Department of Cellular Biochemistry, University Medical Center, 37073, Göttingen, Germany.
Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.
Institute of Pathology, University Medical Center, 37075, Göttingen, Germany.
Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.
Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, 37075, Göttingen, Germany.
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203, Berlin, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital Klinikum rechts der Isar, 81675, München, Germany.
Center for Protein Assemblies (CPA), Technical University of Munich, 85747, Garching, Germany.

癌细胞必须制定策略来适应由内在或外在过程或治疗药物引起的动态变化的压力。代谢适应性对于缓解此类挑战至关重要。考虑到新陈代谢是适应性的中心节点，它重点关注能量传感器，即 AMP 激活蛋白激酶 (AMPK)。在胰腺导管腺癌 (PDAC) 的一个亚型中，发现 AMPK 表达和磷酸化升高。使用结合筛选实验和化学蛋白质组亲和力分析的药物再利用，鉴定并表征了 PF-3758309，最初开发为 PAK4 抑制剂，作为 AMPK 抑制剂。 PF-3758309 在临床前 PDAC 模型（包括原发性患者来源的类器官）中显示出活性。遗传功能丧失实验表明，AMPK 限制了铁死亡的诱导，因此，PF-3758309 治疗恢复了对铁死亡诱导剂的敏感性。这项工作为开发特定的 AMPK 靶向化合物建立了化学支架，并破译了开发针对 PDAC 的基于 AMPK 抑制剂的联合疗法的框架。

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更新日期：2024-06-17

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