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

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen

  • Koen F. W. Hekking*
    Koen F. W. Hekking
    Symeres, 6546BB Nijmegen, The Netherlands
    *Email: [email protected]
  • Sergio Maroto
    Sergio Maroto
    Symeres, 6546BB Nijmegen, The Netherlands
  • Kees van Kekem
    Kees van Kekem
    Symeres, 6546BB Nijmegen, The Netherlands
  • Frank S. Haasjes
    Frank S. Haasjes
    Symeres, 6546BB Nijmegen, The Netherlands
  • Jack C. Slootweg
    Jack C. Slootweg
    Symeres, 6546BB Nijmegen, The Netherlands
  • Patrick G. B. Oude Alink
    Patrick G. B. Oude Alink
    Symeres, 6546BB Nijmegen, The Netherlands
  • Ron Dirks
    Ron Dirks
    Symeres, 6546BB Nijmegen, The Netherlands
    More by Ron Dirks
  • Malvika Sardana
    Malvika Sardana
    Symeres, 6546BB Nijmegen, The Netherlands
  • Marjon G. Bolster
    Marjon G. Bolster
    Symeres, 6546BB Nijmegen, The Netherlands
  • Brian Kuijpers
    Brian Kuijpers
    Symeres, 6546BB Nijmegen, The Netherlands
  • Dennis Smith
    Dennis Smith
    Symeres, 6546BB Nijmegen, The Netherlands
    More by Dennis Smith
  • Robin Doodeman
    Robin Doodeman
    Symeres, 6546BB Nijmegen, The Netherlands
  • Marcel Scheepstra
    Marcel Scheepstra
    Symeres, 6546BB Nijmegen, The Netherlands
  • Birgit Zech
    Birgit Zech
    X-Rx, Inc., New York, New York 10016, United States
    More by Birgit Zech
  • Mark Mulvihill
    Mark Mulvihill
    X-Rx, Inc., New York, New York 10016, United States
  • Louis M. Renzetti
    Louis M. Renzetti
    X-Rx, Inc., New York, New York 10016, United States
  • Lee Babiss
    Lee Babiss
    X-Rx, Inc., New York, New York 10016, United States
    More by Lee Babiss
  • Paolo A. Centrella
    Paolo A. Centrella
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
  • Matthew A. Clark
    Matthew A. Clark
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
  • John W. Cuozzo
    John W. Cuozzo
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
  • Marie-Aude Guié
    Marie-Aude Guié
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
  • Eric Sigel
    Eric Sigel
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
    More by Eric Sigel
  • Sevan Habeshian
    Sevan Habeshian
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
  • Christopher D. Hupp
    Christopher D. Hupp
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
  • Julie Liu
    Julie Liu
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
    More by Julie Liu
  • Heather A. Thomson
    Heather A. Thomson
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
  • Ying Zhang
    Ying Zhang
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
    More by Ying Zhang
  • Anthony D. Keefe*
    Anthony D. Keefe
    X-Chem, Inc., Waltham, Massachusetts 02453, United States
    *Email: [email protected]
  • Gerhard Müller
    Gerhard Müller
    Symeres, 6546BB Nijmegen, The Netherlands
  • , and 
  • Stijn Gremmen
    Stijn Gremmen
    Symeres, 6546BB Nijmegen, The Netherlands
Cite this: J. Med. Chem. 2024, 67, 4, 3039–3065
Publication Date (Web):February 2, 2024
https://doi.org/10.1021/acs.jmedchem.3c02206
Copyright © 2024 American Chemical Society

    Article Views

    1346

    Altmetric

    -

    Citations

    -
    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (2)»

    Abstract

    Abstract Image

    Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein–protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

    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.3c02206.

    • Experimental details combinatorial array synthesis; assay results for all combinatorial compounds; NMR spectra and HPLC traces of key compounds; single-molecule crystallography data for compound 2, including Ortep-drawing; protein–ligand crystallography data for compound 1; and conformational analysis NMR data (PDF)

    • Molecular formula strings for all final compounds (CSV)

    Accession Codes

    Coordinates for compound 1 in complex with Mcl-1 have been deposited into the Protein Data Bank (PDB: 8QSO). The authors will release the atomic coordinates upon article publication.

    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 has not yet been cited by other publications.

    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