ACS Publications. Most Trusted. Most Cited. Most Read
Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2024, 67, 24, 22263-22281
    Article

    Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties
    Click to copy article linkArticle link copied!

    • Pan Chen
      Pan Chen
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
      Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
      More by Pan Chen
    • Yu Zou
      Yu Zou
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
      More by Yu Zou
    • Xiemin Wang
      Xiemin Wang
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Xiemin Wang
    • Zhichao Chen
      Zhichao Chen
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Zhichao Chen
    • Ke Dong
      Ke Dong
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Ke Dong
    • Jun Yang
      Jun Yang
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
      More by Jun Yang
    • Yaqian Cui
      Yaqian Cui
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Yaqian Cui
    • Jing Gu
      Jing Gu
      Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing 400038, China
      More by Jing Gu
    • Xinyi Wu
      Xinyi Wu
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Xinyi Wu
    • Xiaobo Li
      Xiaobo Li
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Xiaobo Li
    • Ying Zhou
      Ying Zhou
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Ying Zhou
    • Mi Guo
      Mi Guo
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Mi Guo
    • Zhiwei Zheng
      Zhiwei Zheng
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
      More by Zhiwei Zheng
      Orcidhttps://orcid.org/0009-0008-7877-2226
    • Qi Chen
      Qi Chen
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Qi Chen
    • Weiwei Zhu
      Weiwei Zhu
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Weiwei Zhu
    • Di Wu
      Di Wu
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      More by Di Wu
      Orcidhttps://orcid.org/0000-0001-5492-6106
    • Lina Yin
      Lina Yin
      School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China
      More by Lina Yin
    • Lingfeng Chen
      Lingfeng Chen
      School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China
      More by Lingfeng Chen
      Orcidhttps://orcid.org/0000-0003-0089-6559
    • Qin Ouyang*
      Qin Ouyang
      Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing 400038, China
      *Email: [email protected]
      More by Qin Ouyang
      Orcidhttps://orcid.org/0000-0002-1161-5102
    • Guang Liang*
      Guang Liang
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
      Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
      School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China
      *Email: [email protected]
      More by Guang Liang
      Orcidhttps://orcid.org/0000-0002-8278-849X
    • Qidong Tang*
      Qidong Tang
      Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
      Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
      Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
      *Email: [email protected]
      More by Qidong Tang
    Other Access OptionsSupporting Information (5)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 24, 22263–22281
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c02401
    Published December 7, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

    Abstract

    Click to copy section linkSection link copied!
    Abstract Image

    Myeloid differentiation primary response 88 (MyD88) plays a central role in inflammatory responses and diseases. However, only a few inhibitors of MyD88 with some limits have been reported currently. Herein, we identified a lead compound (L7) through virtual screening and synthesized twenty-seven L7 derivatives. An optimal compound (A5) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2H-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer A5S showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. A5S had good stability and safety, showed the highest distribution concentration in the lungs, and exhibited good therapeutic effects on LPS-induced and sepsis-induced ALI mouse models. Most importantly, A5S showed advantages in PK properties, and was identified as a promising MyD88 inhibitor with favorable drug-like properties, compared to the only approved MyD88 inhibitor, TJ-M2010-5, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors LM8.

    Copyright © 2024 American Chemical Society

    Subjects

    what are subjects

    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. Add or change your institution or let them know you’d like them to include access.

    Supporting Information

    Click to copy section linkSection link copied!

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02401.

    • Docking analysis of L7 with the MyD88 protein; toxicity study on A1–A9 and B1–B18; circular dichroism spectrum for raw materials 5R and 5S; drug clinical trial approval notice; 1H NMR and 13C NMR spectra of synthesized compounds; and HPLC trace of synthesized compounds; HRMS spectra of synthesized compounds (PDF)

    • Table of molecular formula string (CSV)

    • Docking of L7 with MyD88 from PDB entry 2Z5V (PDB)

    • Docking of A5S with MyD88 from PDB entry 7BER (PDB)

    • Docking of A5R with MyD88 from PDB entry 7BER (PDB)

    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

    Click to copy section linkSection link copied!

    This article has not yet been cited by other publications.

    Download PDF
    Go to Journal of Medicinal Chemistry
    Get e-Alerts
    Get e-Alerts

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 24, 22263–22281
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c02401
    Published December 7, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

    Article Views

    1186

    Altmetric

    -

    Citations

    -
    Learn about these metrics

    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.