确定生物活体系统中的靶标结合。
Determining target engagement in living systems.
机构信息
Abide Therapeutics, San Diego, California, USA.
出版信息
Nat Chem Biol. 2013 Apr;9(4):200-5. doi: 10.1038/nchembio.1211.
Abstract
Chemical probes are critical tools for elucidating the biological functions of proteins and can lead to new medicines for treating disease. The pharmacological validation of protein function requires verification that chemical probes engage their intended targets . Here we discuss technologies, both established and emergent, for measuring target engagement in living systems and propose that determining this parameter should become standard practice for chemical probe and drug discovery programs.
摘要
化学探针是阐明蛋白质生物学功能的关键工具，并可用于开发治疗疾病的新药。蛋白质功能的药理学验证需要验证化学探针是否与它们的预期靶标结合。在这里，我们讨论了用于在活体系统中测量靶标结合的现有技术和新兴技术，并提出确定这一参数应该成为化学探针和药物发现计划的标准实践。
相似文献
1
Determining target engagement in living systems.确定生物活体系统中的靶标结合。
Nat Chem Biol. 2013 Apr;9(4):200-5. doi: 10.1038/nchembio.1211.
2
Target validation using chemical probes.使用化学探针进行靶点验证。
Nat Chem Biol. 2013 Apr;9(4):195-9. doi: 10.1038/nchembio.1197.
3
The why and how of phenotypic small-molecule screens.表型小分子筛选的原理与方法。
Nat Chem Biol. 2013 Apr;9(4):206-9. doi: 10.1038/nchembio.1206.
4
Target identification and mechanism of action in chemical biology and drug discovery.化学生物学和药物发现中的靶标鉴定和作用机制。
Nat Chem Biol. 2013 Apr;9(4):232-40. doi: 10.1038/nchembio.1199.
5
Quantitative, Real-Time Measurements of Intracellular Target Engagement Using Energy Transfer.利用能量转移对细胞内靶点结合进行定量实时测量。
Methods Mol Biol. 2019;1888:45-71. doi: 10.1007/978-1-4939-8891-4_3.
6
Novel activity-based probes for N-acylethanolamine acid amidase.用于N-酰基乙醇胺酸酰胺酶的新型基于活性的探针。
Chem Commun (Camb). 2017 Aug 22;53(86):11810-11813. doi: 10.1039/c7cc06838g.
7
8
System-level analysis of neuroblastoma tumor-initiating cells implicates AURKB as a novel drug target for neuroblastoma.神经母细胞瘤肿瘤起始细胞的系统水平分析提示 AURKB 是神经母细胞瘤的一个新的药物靶点。
Clin Cancer Res. 2010 Sep 15;16(18):4572-82. doi: 10.1158/1078-0432.CCR-10-0627. Epub 2010 Jul 22.
9
Activity-based proteomics in bioanalysis: past, present and future.生物分析中基于活性的蛋白质组学：过去、现在与未来。
Bioanalysis. 2017 May;9(9):671-673. doi: 10.4155/bio-2017-4999. Epub 2017 May 18.
10
Biomarkers in the drug development process: report from workshop discussions.药物研发过程中的生物标志物：研讨会讨论报告
Regul Toxicol Pharmacol. 2008 Nov;52(2):75-6. doi: 10.1016/j.yrtph.2008.05.001. Epub 2008 May 11.
引用本文的文献
1
Ligustilide Suppresses Macrophage-Mediated Intestinal Inflammation and Restores Gut Barrier via EGR1-ADAM17-TNF-α Pathway in Colitis Mice.藁本内酯通过EGR1-ADAM17-TNF-α通路抑制巨噬细胞介导的肠道炎症并恢复结肠炎小鼠的肠道屏障
Research (Wash D C). 2025 Sep 2;8:0864. doi: 10.34133/research.0864. eCollection 2025.
2
PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.PIP4K2C抑制可逆转由SARS-CoV-2诱导的自噬通量损伤。
Nat Commun. 2025 Jul 10;16(1):6397. doi: 10.1038/s41467-025-61759-1.
3
Target Engagement Assays in Early Drug Discovery.早期药物发现中的靶点结合分析
J Med Chem. 2025 Jun 26;68(12):12331-12368. doi: 10.1021/acs.jmedchem.4c03115. Epub 2025 Jun 4.
4
Lessons Learned and Recommendations from a SCOPE Spinal Cord Injury Neurorestorative Clinical Trials Update.《脊髓损伤神经修复临床试验更新的经验教训与建议》。 （注：SCOPE 可能是特定的脊髓损伤神经修复临床试验相关的名称缩写，这里直接保留英文未翻译，具体含义需结合上下文确定）
Neurotrauma Rep. 2025 Mar 5;6(1):210-231. doi: 10.1089/neur.2024.0163. eCollection 2025.
5
NECTIN-4 PET FOR OPTIMIZING ENFORTUMAB VEDOTIN DOSE-RESPONSE IN UROTHELIAL CARCINOMA.NECTIN-4正电子发射断层扫描用于优化恩沃利单抗在尿路上皮癌中的剂量反应。
bioRxiv. 2024 Dec 25:2024.12.25.630315. doi: 10.1101/2024.12.25.630315.
6
Target Identification of Marine Natural Product Odoamide:Odoamide Induces Apoptotic Cell Death by Targeting ATPase Na/K Transporting Subunit Alpha 1 (ATP1A1).海洋天然产物奥多酰胺的靶点鉴定：奥多酰胺通过靶向ATP酶钠/钾转运亚基α1（ATP1A1）诱导细胞凋亡性死亡。
Chembiochem. 2025 Mar 15;26(6):e202400762. doi: 10.1002/cbic.202400762. Epub 2025 Jan 24.
7
Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants.合成17β-羟类固醇脱氢酶13（17B-HSD13）底物的设计与应用揭示了人类保护性变体的保留催化活性。
Nat Commun. 2025 Jan 2;16(1):297. doi: 10.1038/s41467-024-54487-5.
8
Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM.利用CeTEAM将细胞药物靶点结合与下游药理学联系起来。
Nat Commun. 2024 Dec 6;15(1):10347. doi: 10.1038/s41467-024-54415-7.
9
Insights into the use of biomarkers in clinical trials in Alzheimer's disease.浅析生物标志物在阿尔茨海默病临床试验中的应用。
EBioMedicine. 2024 Oct;108:105322. doi: 10.1016/j.ebiom.2024.105322. Epub 2024 Oct 3.
10
Labeling of CC Chemokine Receptor 2 with a Versatile Intracellular Allosteric Probe.用多功能细胞内变构探针标记 CC 趋化因子受体 2。
ACS Chem Biol. 2024 Sep 20;19(9):2070-2080. doi: 10.1021/acschembio.4c00439. Epub 2024 Aug 26.
本文引用的文献
1
Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.在黑色素瘤中建立vemurafenib 耐药模型揭示了一种预防耐药的策略。
Nature. 2013 Feb 14;494(7436):251-5. doi: 10.1038/nature11814. Epub 2013 Jan 9.
2
Functional imaging of legumain in cancer using a new quenched activity-based probe.利用新型猝灭活性探针对 legumain 在癌症中的功能成像。
J Am Chem Soc. 2013 Jan 9;135(1):174-82. doi: 10.1021/ja307083b. Epub 2012 Dec 18.
3
DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses.DAGLβ 抑制作用破坏了参与巨噬细胞炎症反应的脂质网络。
Nat Chem Biol. 2012 Dec;8(12):999-1007. doi: 10.1038/nchembio.1105. Epub 2012 Oct 28.
4
Brain Penetrant LRRK2 Inhibitor.脑渗透性LRRK2抑制剂。
ACS Med Chem Lett. 2012 Aug 9;3(8):658-662. doi: 10.1021/ml300123a. Epub 2012 Jun 18.
5
Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.布鲁顿酪氨酸激酶抑制剂伊布替尼（PCI-32765）在复发/难治性 B 细胞恶性肿瘤患者中具有显著的活性。
J Clin Oncol. 2013 Jan 1;31(1):88-94. doi: 10.1200/JCO.2012.42.7906. Epub 2012 Oct 8.
6
Clinical perspectives for irreversible tyrosine kinase inhibitors in cancer.癌症中不可逆酪氨酸激酶抑制剂的临床观点。
Biochem Pharmacol. 2012 Dec 1;84(11):1388-99. doi: 10.1016/j.bcp.2012.07.031. Epub 2012 Aug 4.
7
Confirming target engagement for reversible inhibitors in vivo by kinetically tuned activity-based probes.通过动力学调节的基于活性的探针在体内证实可逆抑制剂的靶标结合。
J Am Chem Soc. 2012 Jun 27;134(25):10345-8. doi: 10.1021/ja303400u. Epub 2012 Jun 12.
8
Activity-based probes for studying the activity of flavin-dependent oxidases and for the protein target profiling of monoamine oxidase inhibitors.用于研究黄素依赖型氧化酶活性以及单胺氧化酶抑制剂的蛋白质靶标分析的基于活性的探针。
Angew Chem Int Ed Engl. 2012 Jul 9;51(28):7035-40. doi: 10.1002/anie.201201955. Epub 2012 Jun 11.
9
A nonpeptidic cathepsin S activity-based probe for noninvasive optical imaging of tumor-associated macrophages.一种基于组织蛋白酶S活性的非肽类探针，用于肿瘤相关巨噬细胞的无创光学成像。
Chem Biol. 2012 May 25;19(5):619-28. doi: 10.1016/j.chembiol.2012.03.012.
10
The synthesis and in vivo evaluation of [18F]PF-9811: a novel PET ligand for imaging brain fatty acid amide hydrolase (FAAH).[18F]PF-9811 的合成及体内评价：一种新型用于脑脂肪酸酰胺水解酶（FAAH）成像的 PET 配体。
Nucl Med Biol. 2012 Oct;39(7):1058-67. doi: 10.1016/j.nucmedbio.2012.03.011. Epub 2012 May 8.
Zotero 插件