强效、口服有效的小分子 MDM2-p53 相互作用抑制剂。
Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.
机构信息
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
出版信息
J Med Chem. 2009 Dec 24;52(24):7970-3. doi: 10.1021/jm901400z.
Abstract
We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
摘要
我们在此报告了强效和口服活性的 MDM2-p53 相互作用小分子抑制剂的设计。化合物 5 与 MDM2 的结合 Ki 值为 0.6 nM，在低至 40 nM 的浓度下即可激活 p53，并在野生型 p53 的肿瘤细胞中比在突变/缺失 p53 的肿瘤细胞中更有效地选择性抑制细胞生长。化合物 5 具有良好的口服生物利用度，能有效地抑制 SJSA-1 异种移植模型中的肿瘤生长。
相似文献
1
Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.强效、口服有效的小分子 MDM2-p53 相互作用抑制剂。
J Med Chem. 2009 Dec 24;52(24):7970-3. doi: 10.1021/jm901400z.
2
Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles.利用螺环氧化吲哚中的逆曼尼希开环-环化反应机制设计化学稳定、高效且有效的MDM2抑制剂。
J Med Chem. 2014 Dec 26;57(24):10486-98. doi: 10.1021/jm501541j. Epub 2014 Dec 12.
3
A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice.一种强效的 MDM2-p53 相互作用小分子抑制剂（MI-888）在小鼠中实现了完全和持久的肿瘤消退。
J Med Chem. 2013 Jul 11;56(13):5553-61. doi: 10.1021/jm4005708. Epub 2013 Jun 20.
4
Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors.具有高度效力和疗效的非对映体螺环氧化吲哚作为 MDM2 抑制剂。
J Am Chem Soc. 2013 May 15;135(19):7223-34. doi: 10.1021/ja3125417. Epub 2013 May 3.
5
Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition.一种特定的MDM2抑制剂对p53的短暂激活对肿瘤具有选择性毒性，并导致肿瘤生长完全抑制。
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3933-8. doi: 10.1073/pnas.0708917105. Epub 2008 Mar 3.
6
MI-63: a novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53.MI-63：一种靶向MDM2的新型小分子抑制剂，可诱导具有野生型p53的胚胎性和肺泡性横纹肌肉瘤细胞凋亡。
Br J Cancer. 2009 Sep 1;101(5):774-81. doi: 10.1038/sj.bjc.6605199.
7
A fluorinated indole-based MDM2 antagonist selectively inhibits the growth of p53 osteosarcoma cells.一种基于氟吲哚的 MDM2 拮抗剂，能选择性抑制 p53 成骨肉瘤细胞的生长。
FEBS J. 2019 Apr;286(7):1360-1374. doi: 10.1111/febs.14774. Epub 2019 Feb 16.
8
Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction.基于结构的螺环氧化吲哚类化合物设计，作为MDM2-p53相互作用的强效、特异性小分子抑制剂。
J Med Chem. 2006 Jun 15;49(12):3432-5. doi: 10.1021/jm051122a.
9
SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression.SAR405838：一种优化的MDM2与p53相互作用抑制剂，可诱导肿瘤完全且持久消退。
Cancer Res. 2014 Oct 15;74(20):5855-65. doi: 10.1158/0008-5472.CAN-14-0799. Epub 2014 Aug 21.
10
Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran-oxindole derivatives as potent p53-MDM2 inhibitors.新型抗肿瘤螺四氢噻喃-氧化吲哚衍生物作为高效p53-MDM2抑制剂的设计、合成及生物学评价
Bioorg Med Chem. 2017 Oct 15;25(20):5268-5277. doi: 10.1016/j.bmc.2017.07.049. Epub 2017 Jul 28.
引用本文的文献
1
MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.MDM2 抑制剂在癌症治疗中的应用：过去、现在与未来。
Pharmacol Rev. 2024 May 2;76(3):414-453. doi: 10.1124/pharmrev.123.001026.
2
Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3'-oxindoles] under Microwave Irradiation and Their Anticancer Activity.微波辐射下新型功能化螺[吡咯烷-2,3'-氧吲哚]的 chemo-/Regio-选择性合成及其抗癌活性。
Molecules. 2023 Sep 7;28(18):6503. doi: 10.3390/molecules28186503.
3
Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials.靶向 p53-MDM2 相互作用的小分子抑制剂：从临床试验中的 MDM2 抑制剂中获得的启示。
J Hematol Oncol. 2022 Jul 13;15(1):91. doi: 10.1186/s13045-022-01314-3.
4
PROTAC Degraders with Ligands Recruiting MDM2 E3 Ubiquitin Ligase: An Updated Perspective.通过招募MDM2 E3泛素连接酶的配体构建的PROTAC降解剂：最新观点
Acta Mater Med. 2022;1(2):244-259. doi: 10.15212/amm-2022-0010. Epub 2022 May 31.
5
Spirocyclic derivatives as antioxidants: a review.螺环衍生物作为抗氧化剂：综述
RSC Adv. 2021 Jun 21;11(36):21926-21954. doi: 10.1039/d1ra01170g.
6
Activity-Directed Synthesis of Inhibitors of the p53/hDM2 Protein-Protein Interaction.基于活性的 p53/hDM2 蛋白-蛋白相互作用抑制剂的合成。
Chemistry. 2020 Aug 21;26(47):10682-10689. doi: 10.1002/chem.202002153. Epub 2020 Aug 4.
7
Recent Synthetic Approaches towards Small Molecule Reactivators of p53.近期小分子 p53 激活剂的合成方法研究进展
Biomolecules. 2020 Apr 20;10(4):635. doi: 10.3390/biom10040635.
8
Correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility: An updated meta-analysis.MDM2 T309G 单核苷酸多态性与食管癌易感性的相关性：一项更新的荟萃分析。
Thorac Cancer. 2020 Mar;11(3):672-678. doi: 10.1111/1759-7714.13316. Epub 2020 Jan 22.
9
Inhibition of p53 inhibitors: progress, challenges and perspectives.p53 抑制剂的抑制：进展、挑战和展望。
J Mol Cell Biol. 2019 Jul 19;11(7):586-599. doi: 10.1093/jmcb/mjz075.
10
An Efficient Synthesis of Spiro[indoline-3,9'-xanthene]trione Derivatives Catalyzed by Magnesium Perchlorate.高氯酸镁催化高效合成螺[吲哚啉-3,9'-呫吨]三酮衍生物
Molecules. 2017 Aug 4;22(8):1295. doi: 10.3390/molecules22081295.
本文引用的文献
1
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy.MDM2-p53 蛋白-蛋白相互作用的小分子抑制剂以重新激活 p53 功能：一种癌症治疗的新方法。
Annu Rev Pharmacol Toxicol. 2009;49:223-41. doi: 10.1146/annurev.pharmtox.48.113006.094723.
2
Targeting the MDM2-p53 interaction for cancer therapy.靶向MDM2-p53相互作用用于癌症治疗。
Clin Cancer Res. 2008 Sep 1;14(17):5318-24. doi: 10.1158/1078-0432.CCR-07-5136.
3
Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer.一种特定的MDM2拮抗剂（MI-43）使p53重新激活，导致p21介导的细胞周期停滞以及结肠癌中的选择性细胞死亡。
Mol Cancer Ther. 2008 Jun;7(6):1533-42. doi: 10.1158/1535-7163.MCT-08-0140.
4
Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition.一种特定的MDM2抑制剂对p53的短暂激活对肿瘤具有选择性毒性，并导致肿瘤生长完全抑制。
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3933-8. doi: 10.1073/pnas.0708917105. Epub 2008 Mar 3.
5
Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia.综合生物标志物和基因组分析确定p53状态是慢性淋巴细胞白血病对MDM2抑制剂反应的主要决定因素。
Blood. 2008 Feb 1;111(3):1584-93. doi: 10.1182/blood-2007-09-112698. Epub 2007 Oct 30.
6
Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models.基于整体受体模型发现的MDM2-p53相互作用的小分子抑制剂。
J Am Chem Soc. 2007 Oct 24;129(42):12809-14. doi: 10.1021/ja073687x. Epub 2007 Sep 29.
7
MDM2 inhibitors for cancer therapy.用于癌症治疗的MDM2抑制剂。
Trends Mol Med. 2007 Jan;13(1):23-31. doi: 10.1016/j.molmed.2006.11.002. Epub 2006 Nov 28.
8
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold.基于异吲哚啉酮支架的MDM2-p53蛋白质-蛋白质相互作用的小分子抑制剂。
J Med Chem. 2006 Oct 19;49(21):6209-21. doi: 10.1021/jm0601194.
9
Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy.通过综合虚拟数据库筛选策略发现一种纳摩尔级别的人鼠双微体2（MDM2）-p53相互作用抑制剂。
J Med Chem. 2006 Jun 29;49(13):3759-62. doi: 10.1021/jm060023+.
10
Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction.基于结构的螺环氧化吲哚类化合物设计，作为MDM2-p53相互作用的强效、特异性小分子抑制剂。
J Med Chem. 2006 Jun 15;49(12):3432-5. doi: 10.1021/jm051122a.
Zotero 插件