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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2019, 62, 22, 10258-10271
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Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere

  • Gwenaella Rescourio*
    Gwenaella Rescourio
    Departments of Medicinal Chemistry, Amgen Research, 360 Binney Street, Cambridge, Massachusetts 02142, United States
    *E-mail: [email protected]
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    Orcidhttp://orcid.org/0000-0002-4678-9591
  • , 
  • Ana Z. Gonzalez
    Ana Z. Gonzalez
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Salman Jabri
    Salman Jabri
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Brian Belmontes
    Brian Belmontes
    Departments of Oncology Research, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States
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  • , 
  • Gordon Moody
    Gordon Moody
    Departments of Oncology Research, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States
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  • , 
  • Doug Whittington
    Doug Whittington
    Molecular Engineering, Amgen Research, 360 Binney Street, Cambridge, Massachusetts 02142, United States
    More by Doug Whittington
  • , 
  • Xin Huang
    Xin Huang
    Molecular Engineering, Amgen Research, 360 Binney Street, Cambridge, Massachusetts 02142, United States
    More by Xin Huang
  • , 
  • Sean Caenepeel
    Sean Caenepeel
    Departments of Oncology Research, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States
    More by Sean Caenepeel
  • , 
  • Mario Cardozo
    Mario Cardozo
    Molecular Engineering, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Alan C. Cheng
    Alan C. Cheng
    Molecular Engineering, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • David Chow
    David Chow
    Discovery Attribute Sciences, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Hannah Dou
    Hannah Dou
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Adrie Jones
    Adrie Jones
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Ron C. Kelly
    Ron C. Kelly
    Drug Product Technologies, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States
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  • , 
  • Yihong Li
    Yihong Li
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Mike Lizarzaburu
    Mike Lizarzaburu
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Mei-Chu Lo
    Mei-Chu Lo
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Rommel Mallari
    Rommel Mallari
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Cesar Meleza
    Cesar Meleza
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Yosup Rew
    Yosup Rew
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Scott Simonovich
    Scott Simonovich
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Daqing Sun
    Daqing Sun
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Simon Turcotte
    Simon Turcotte
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Xuelei Yan
    Xuelei Yan
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
    More by Xuelei Yan
  • , 
  • Simon G. Wong
    Simon G. Wong
    Pharmacokinetics and Drug Metabolism, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
    More by Simon G. Wong
  • , 
  • Evelyn Yanez
    Evelyn Yanez
    Drug Product Technologies, Process Development, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
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  • , 
  • Manuel Zancanella
    Manuel Zancanella
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
    More by Manuel Zancanella
  • , 
  • Jonathan Houze
    Jonathan Houze
    Departments of Medicinal Chemistry, Amgen Research, 360 Binney Street, Cambridge, Massachusetts 02142, United States
    More by Jonathan Houze
  • , 
  • Julio C. Medina
    Julio C. Medina
    Departments of Medicinal Chemistry, Amgen Research, 1120 Veterans Boulevard, South San Francisco, California 94080, United States
    More by Julio C. Medina
  • , 
  • Paul E. Hughes
    Paul E. Hughes
    Departments of Oncology Research, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States
    More by Paul E. Hughes
  • , and 
  • Sean P. Brown
    Sean P. Brown
    Medicinal Chemistry, Amgen Research, One Amgen Center Drive, Thousand Oaks, California 91320, United States
    More by Sean P. Brown
    Orcidhttp://orcid.org/0000-0002-8218-002X
Cite this: J. Med. Chem. 2019, 62, 22, 10258–10271
Publication Date (Web):November 18, 2019
https://doi.org/10.1021/acs.jmedchem.9b01310
Copyright © 2019 American Chemical Society
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Supporting Info (2)»
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Abstract

Abstract Image

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b01310.

  • (i) In vitro biological assays, (ii) in vivo protocols, (iii) procedures and experimental data for compounds 4–9, 11, 13, 16–19, 21–29, 40, 42–43, (iv) determination of cocrystal structures of 1, 3, 5, 7, 8, 10, and 20 bound to Mcl-1 (PDF)

  • Molecular formula strings and associated biochemical and cellular data (CSV)

Accession Codes

The cocrystal structures of 1, 3, 5, 7, 8, 10, and 20 with Mcl-1 have been deposited in the PDB with accession codes 6UD2, 6UDV, 6UDY, 6UDX, 6UDU, 6UDT, and 6UDI. Authors will release the atomic coordinates upon article publication.

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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 8 publications.

  1. Peng-Ju Zhu, Ze-Zhou Yu, Yi-Fei Lv, Jing-Long Zhao, Yuan-Yuan Tong, Qi-Dong You, Zheng-Yu Jiang. Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability. Journal of Medicinal Chemistry 2021, 64 (15) , 11330-11353. https://doi.org/10.1021/acs.jmedchem.1c00682
  2. Jingjing Liu, Fangkui Yin, Ziqian Wang, Ting Song, Zhichao Zhang. An updated patent review of Mcl-1 inhibitors (2020–2022). Expert Opinion on Therapeutic Patents 2023, 80 https://doi.org/10.1080/13543776.2023.2219394
  3. Hongguang Deng, Min Huang, Hui Liu, Hong Zhang, Liang Liu, Bensheng Gao, Xianlu Li, Jinbo Li, Qun Niu, Zhenwei Zhang, Shenglin Luan, Jingyi Zhang, Yongkui Jing, Dan Liu, Linxiang Zhao. Development of a series of novel Mcl-1 inhibitors bearing an indole carboxylic acid moiety. Bioorganic Chemistry 2022, 127 , 106018. https://doi.org/10.1016/j.bioorg.2022.106018
  4. Sarah T. Diepstraten, Mary Ann Anderson, Peter E. Czabotar, Guillaume Lessene, Andreas Strasser, Gemma L. Kelly. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nature Reviews Cancer 2022, 22 (1) , 45-64. https://doi.org/10.1038/s41568-021-00407-4
  5. Kexue Li. Interdiction at a protein-protein interface: MCL-1 inhibitors for oncology. Bioorganic & Medicinal Chemistry Letters 2021, 32 , 127717. https://doi.org/10.1016/j.bmcl.2020.127717
  6. Arvind Negi, Paul V. Murphy. Development of Mcl-1 inhibitors for cancer therapy. European Journal of Medicinal Chemistry 2021, 210 , 113038. https://doi.org/10.1016/j.ejmech.2020.113038
  7. Karson J. Kump, Zaneta Nikolovska-Coleska. Discovery and Development of Mcl-1 Inhibitors as Anti-cancer Therapeutics: Hit to Clinical Candidate Optimization. 2020, 171-208. https://doi.org/10.1039/9781788016544-00171
  8. Shovan Mondal, Suniti Malakar. Synthesis of sulfonamide and their synthetic and therapeutic applications: Recent advances. Tetrahedron 2020, 76 (48) , 131662. https://doi.org/10.1016/j.tet.2020.131662

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