ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction

  • Gianni Chessari*
    Gianni Chessari
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    *Email: [email protected]
  • Ian R. Hardcastle*
    Ian R. Hardcastle
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
    *Email: [email protected]
  • Jong Sook Ahn
    Jong Sook Ahn
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Burcu Anil
    Burcu Anil
    Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
    More by Burcu Anil
  • Elizabeth Anscombe
    Elizabeth Anscombe
    Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
  • Ruth H. Bawn
    Ruth H. Bawn
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
    More by Ruth H. Bawn
  • Luke D. Bevan
    Luke D. Bevan
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Timothy J. Blackburn
    Timothy J. Blackburn
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Ildiko Buck
    Ildiko Buck
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    More by Ildiko Buck
  • Celine Cano
    Celine Cano
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
    More by Celine Cano
  • Benoit Carbain
    Benoit Carbain
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Juan Castro
    Juan Castro
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    More by Juan Castro
  • Ben Cons
    Ben Cons
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    More by Ben Cons
  • Sarah J. Cully
    Sarah J. Cully
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Jane A. Endicott
    Jane A. Endicott
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
  • Lynsey Fazal
    Lynsey Fazal
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    More by Lynsey Fazal
  • Bernard T. Golding
    Bernard T. Golding
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Roger J. Griffin
    Roger J. Griffin
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Karen Haggerty
    Karen Haggerty
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Suzannah J. Harnor
    Suzannah J. Harnor
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Keisha Hearn
    Keisha Hearn
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    More by Keisha Hearn
  • Stephen Hobson
    Stephen Hobson
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Rhian S. Holvey
    Rhian S. Holvey
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Steven Howard
    Steven Howard
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Claire E. Jennings
    Claire E. Jennings
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
  • Christopher N. Johnson
    Christopher N. Johnson
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • John Lunec
    John Lunec
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
    More by John Lunec
  • Duncan C. Miller
    Duncan C. Miller
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • David R. Newell
    David R. Newell
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
  • Martin E. M. Noble
    Martin E. M. Noble
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
  • Judith Reeks
    Judith Reeks
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    More by Judith Reeks
  • Charlotte H. Revill
    Charlotte H. Revill
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • Christiane Riedinger
    Christiane Riedinger
    Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
  • Jeffrey D. St. Denis
    Jeffrey D. St. Denis
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Emiliano Tamanini
    Emiliano Tamanini
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Huw Thomas
    Huw Thomas
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
    More by Huw Thomas
  • Neil T. Thompson
    Neil T. Thompson
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Mladen Vinković
    Mladen Vinković
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Stephen R. Wedge
    Stephen R. Wedge
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
  • Pamela A. Williams
    Pamela A. Williams
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Nicola E. Wilsher
    Nicola E. Wilsher
    Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Bian Zhang
    Bian Zhang
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
    More by Bian Zhang
  • , and 
  • Yan Zhao
    Yan Zhao
    Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, U.K.
    More by Yan Zhao
Cite this: J. Med. Chem. 2021, 64, 7, 4071–4088
Publication Date (Web):March 24, 2021
https://doi.org/10.1021/acs.jmedchem.0c02188
Copyright © 2021 American Chemical Society

    Article Views

    4848

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (4)»

    Abstract

    Abstract Image

    Inhibition of murine double minute 2 (MDM2)-p53 protein–protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02188.

    • Molecular formula string (CSV)

    • Model of the X-ray crystal structure of MDM2 with compound 4 (CIF)

    • Structure factors of the X-ray crystal structure of MDM2 with compound 4 (CIF)

    • Additional experimental details for compounds not included in the main section and analytical data for all compounds and intermediates; NMR studies on 5; X-ray structure tables; and computational chemistry (PDF)

    Accession Codes

    Coordinates for MDM2 complexes with compounds 1, 5, 13, 14, and 23 have been deposited in the Protein Data Bank (PDB) under accession codes 7BJ0, 7BMG, 7BJ6, 7BIV, and 7BIR, respectively. Coordinates for the small molecule crystal structure of compound 18 have been deposited in the CCDC/FIZ Karlsruhe database under the deposition number 2059877.

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 32 publications.

    1. Jing Cheng, Ziqin Yan, Kailong Jiang, Chen Liu, Dehua Xu, Xilin Lyu, Xiaobei Hu, Shiyan Zhang, Yubo Zhou, Jia Li, Yujun Zhao. Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein–Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy. Journal of Medicinal Chemistry 2023, 66 (24) , 16991-17025. https://doi.org/10.1021/acs.jmedchem.3c01815
    2. Jiaqi Yan, Yongzheng Ding, Hanmin Huang. Palladium-Catalyzed Chemodivergent Carbonylation of ortho-Bromoarylimine to Biisoindolinones and Spiroisoindolinones. The Journal of Organic Chemistry 2023, 88 (8) , 5194-5204. https://doi.org/10.1021/acs.joc.2c02170
    3. Arti Sharma, Prince Anand, Yogendra S. Padwad, Sushil K. Maurya. Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells. ACS Omega 2022, 7 (49) , 45036-45044. https://doi.org/10.1021/acsomega.2c05378
    4. Benjamin D. Cons, David G. Twigg, Rajendra Kumar, Gianni Chessari. Electrostatic Complementarity in Structure-Based Drug Design. Journal of Medicinal Chemistry 2022, 65 (11) , 7476-7488. https://doi.org/10.1021/acs.jmedchem.2c00164
    5. Shiyan Zhang, Ziqin Yan, Yafang Li, Yang Gong, Xilin Lyu, Jianfeng Lou, Daizhou Zhang, Xiangjing Meng, Yujun Zhao. Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells. Journal of Medicinal Chemistry 2022, 65 (8) , 6207-6230. https://doi.org/10.1021/acs.jmedchem.2c00095
    6. Chamandi S. Dampalla, Yunjeong Kim, Naemi Bickmeier, Athri D. Rathnayake, Harry Nhat Nguyen, Jian Zheng, Maithri M. Kashipathy, Matthew A. Baird, Kevin P. Battaile, Scott Lovell, Stanley Perlman, Kyeong-Ok Chang, William C. Groutas. Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease. Journal of Medicinal Chemistry 2021, 64 (14) , 10047-10058. https://doi.org/10.1021/acs.jmedchem.1c00319
    7. Khedidja Benarous, Talia Serseg, Arif Mermer, Aydin Tahmasebifar, Houssem Boulebd, Abderahmane Linani. Exploring the Anti‐Cancer Potential of Hispidin: A Comprehensive in Silico and in Vitro Study on Human Osteosarcoma Saos2 Cells. Chemistry & Biodiversity 2024, 33 https://doi.org/10.1002/cbdv.202301833
    8. Zhitong Lin, Chen Liu, Ziqin Yan, Jing Cheng, Xiancheng Wang, Feilong Zhou, Xilin Lyu, Shiyan Zhang, Daizhou Zhang, Xiangjing Meng, Yujun Zhao. Synthesis and biological evaluation of 4-imidazolidinone–containing compounds as potent inhibitors of the MDM2/p53 interaction. European Journal of Medicinal Chemistry 2024, 270 , 116366. https://doi.org/10.1016/j.ejmech.2024.116366
    9. Qiansong Gao, Lianyou Zheng, Shulin Ning, Lingling Shi, Cheng Wu, Mian Liu, Jinbao Xiang. Electroselective C(sp 3 )–H deuteration of isoindolinones. Organic Chemistry Frontiers 2023, 10 (24) , 6212-6218. https://doi.org/10.1039/D3QO01782F
    10. Christian Bailly. Discovery and current developments of isoindolinone-based fungal natural products. European Journal of Medicinal Chemistry Reports 2023, 9 , 100112. https://doi.org/10.1016/j.ejmcr.2023.100112
    11. Doğukan Doyduk, Burak Derkus, Buse Sari, Cemil Can Eylem, Emirhan Nemutlu, Yılmaz Yıldırır. Molecular docking, synthesis, anticancer activity, and metabolomics study of boronic acid ester‐containing fingolimod derivatives. Archiv der Pharmazie 2023, 356 (12) https://doi.org/10.1002/ardp.202300382
    12. Yanyu Jiang, Shuaishuai Ni, Biying Xiao, Lijun Jia. Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy. Acta Pharmaceutica Sinica B 2023, 13 (11) , 4341-4372. https://doi.org/10.1016/j.apsb.2023.07.019
    13. Yile Liao, Yu Gui, Qingzhou Li, Jun An, Dong Wang. The signaling pathways and targets of natural products from traditional Chinese medicine treating gastric cancer provide new candidate therapeutic strategies. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2023, 1878 (6) , 188998. https://doi.org/10.1016/j.bbcan.2023.188998
    14. Neha Bhatia, Rakesh Khator, Swanand Kulkarni, Yogesh Singh, Pradeep Kumar, Suresh Thareja. Recent Advancements in the Discovery of MDM2/MDM2-p53 Interaction Inhibitors for the Treatment of Cancer. Current Medicinal Chemistry 2023, 30 (32) , 3668-3701. https://doi.org/10.2174/0929867330666221114103924
    15. Hui Zhang, Huanli Zhang, Jingchun Wang, Li Fan, Weijie Mu, Yingxue Jin, Zhiqiang Wang. Small-molecular cyclic peptide exerts viability suppression effects on HepG2 cells via triggering p53 apoptotic pathways. Chemico-Biological Interactions 2023, 382 , 110633. https://doi.org/10.1016/j.cbi.2023.110633
    16. Rita Maria Concetta Di Martino, Brad D. Maxwell, Tracey Pirali. Deuterium in drug discovery: progress, opportunities and challenges. Nature Reviews Drug Discovery 2023, 22 (7) , 562-584. https://doi.org/10.1038/s41573-023-00703-8
    17. Lei Zhao, Tingting Li, Hongyu Xu, Xiong Zhang, Huiming Lin, Na Liu, Yingxue Jin, Zhiqiang Wang. Molecular electrostatic potential and volume-aided drug design based on the isoindolinone-containing cyclopeptide S-PK6. New Journal of Chemistry 2023, 47 (20) , 9806-9818. https://doi.org/10.1039/D3NJ01202F
    18. Xiong Zhang, Tingting Li, Lei Zhao, Hongyu Xu, Chang Yan, Yingxue Jin, Zhiqiang Wang. DFT-aided infrared and electronic circular dichroism spectroscopic study of cyclopeptide S-PK6 and the exploration of its antitumor potential by molecular docking. Journal of Molecular Structure 2023, 1278 , 134903. https://doi.org/10.1016/j.molstruc.2023.134903
    19. Lishuang Zhao, Liguo Wei, Xuewei Li, Huixin Chen, Jialing Liu, Xujian Wang, Fujing Guan. Design and synthesis of novel cyclopeptide p53-MDM2 inhibitors with isoindolinone as antitumor agent. Journal of Molecular Structure 2023, 1275 , 134604. https://doi.org/10.1016/j.molstruc.2022.134604
    20. Meysam Talebi, Shahin Boumi, Maryam Sadat Nezamtaheri, Yeganeh Sarmad, Faezeh Sadat Hosseini, Ladan Delphi, Bahram Goliaei, Mohsen Amini, Massoud Amanlou. Synthesis, Docking Study, and Biological Evaluation of 2‐Phenylchroman‐4‐one Derivatives as Murine Double Minute 2 (MDM2) Inhibitors. ChemistrySelect 2023, 8 (3) https://doi.org/10.1002/slct.202204044
    21. Upendra Chaudhary, Vijay Gurung, Sayed Tariq Pachakhan, Jhashanath Adhikari Subin, Yuba Raj Pokharel, Paras Nath Yadav. Evaluation of Anticancer Potential of N(4)-Alkyl Substituted 5-Methoxyisatin Thiosemicarbazones: Synthesis, Characterization and Molecular Docking. Asian Journal of Chemistry 2023, 35 (3) , 605-616. https://doi.org/10.14233/ajchem.2023.26967
    22. Ana Maria Montagut, Marc Armengol, Gema Gorjón de Pablo, Roger Estrada-Tejedor, José Ignacio Borrell, Gaël Roué. Recent advances in the pharmacological targeting of ubiquitin-regulating enzymes in cancer. Seminars in Cell & Developmental Biology 2022, 132 , 213-229. https://doi.org/10.1016/j.semcdb.2022.02.007
    23. Elisa Nuti, Valeria La Pietra, Simona Daniele, Doretta Cuffaro, Lidia Ciccone, Chiara Giacomelli, Carolina Cason, Alfonso Carotenuto, Vincenzo Maria D’Amore, Eleonora Da Pozzo, Barbara Costa, Riccardo Di Leo, Manola Comar, Luciana Marinelli, Claudia Martini, Armando Rossello. Identification of a Novel p53 Modulator Endowed with Antitumoural and Antibacterial Activity through a Scaffold Repurposing Approach. Pharmaceuticals 2022, 15 (11) , 1318. https://doi.org/10.3390/ph15111318
    24. Gabriel C. Veríssimo, Mateus Sá M. Serafim, Thales Kronenberger, Rafaela S. Ferreira, Kathia M. Honorio, Vinícius G. Maltarollo. Designing drugs when there is low data availability: one-shot learning and other approaches to face the issues of a long-term concern. Expert Opinion on Drug Discovery 2022, 17 (9) , 929-947. https://doi.org/10.1080/17460441.2022.2114451
    25. Xiaoyu Zhao, Danyang Xiong, Song Luo, Lili Duan. Molecular investigation of the dual inhibition mechanism for targeted P53 regulator MDM2/MDMX inhibitors. Physical Chemistry Chemical Physics 2022, 24 (27) , 16799-16815. https://doi.org/10.1039/D2CP01780F
    26. Ahmed Elwakeel. Abrogating the Interaction Between p53 and Mortalin (Grp75/HSPA9/mtHsp70) for Cancer Therapy: The Story so far. Frontiers in Cell and Developmental Biology 2022, 10 https://doi.org/10.3389/fcell.2022.879632
    27. Shimei Xiao, Lishuang Zhao, Rui Yan, Huanli Zhang, Jiawen Liu, Zhiqiang Wang, Guanghui Tan, Yingxue Jin. Efficient synthesis of bisulfide-bridged bicyclopeptides by intramolecular photoinduced electron transfer cycloreaction. New Journal of Chemistry 2022, 46 (13) , 6366-6370. https://doi.org/10.1039/D2NJ00583B
    28. Huifang Lai, Jiexin Xu, Jin Lin, Biling Su, Daijun Zha. Chemo-selective control of Ritter-type reaction by coordinatively unsaturated inorganic salt hydrates. Organic Chemistry Frontiers 2022, 9 (6) , 1541-1549. https://doi.org/10.1039/D1QO01832A
    29. Yan-Ling Chen, Zi-Mu Zhang, Xiao-Lu Li, Yan-Fang Tao, Shui-Yan Wu, Fang Fang, Yi Xie, Xin-Mei Liao, Gen Li, Di Wu, Hai-Rong Wang, Ran Zuo, Hai-Bo Cao, Jing-Jing Pan, Juan-Juan Yu, Zheng Zhang, Xin-Ran Chu, Yong-Ping Zhang, Chen-Xi Feng, Jian-Wei Wang, Jun Lu, Shao-Yan Hu, Zhi-Heng Li, Jian Pan. MI‑773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1. Oncology Letters 2021, 22 (6) https://doi.org/10.3892/ol.2021.13099
    30. Feng Jiang, Xiao-Lin Miao, Xiao-Tian Zhang, Feng Yan, Yan Mao, Chu-Yan Wu, Guo-Ping Zhou, . A Hypoxia Gene-Based Signature to Predict the Survival and Affect the Tumor Immune Microenvironment of Osteosarcoma in Children. Journal of Immunology Research 2021, 2021 , 1-13. https://doi.org/10.1155/2021/5523832
    31. Yingqian Chen, Runzhi Liu, Wei Wang, Chen Wang, Ning Zhang, Xuejing Shao, Qiaojun He, Meidan Ying. Advances in targeted therapy for osteosarcoma based on molecular classification. Pharmacological Research 2021, 169 , 105684. https://doi.org/10.1016/j.phrs.2021.105684
    32. Dehua Yu, Zhiyuan Xu, Xiangdong Cheng, Jiangjiang Qin. The role of miRNAs in MDMX‐p53 interplay. Journal of Evidence-Based Medicine 2021, 14 (2) , 152-160. https://doi.org/10.1111/jebm.12428

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect