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The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

Author

Listed:
  • András Kotschy

    (Servier Research Institute of Medicinal Chemistry)

  • Zoltán Szlavik

    (Servier Research Institute of Medicinal Chemistry)

  • James Murray

    (Vernalis (R&D) Ltd.)

  • James Davidson

    (Vernalis (R&D) Ltd.)

  • Ana Leticia Maragno

    (Institut de Recherches Servier Oncology R&D Unit)

  • Gaëtane Le Toumelin-Braizat

    (Institut de Recherches Servier Oncology R&D Unit)

  • Maïa Chanrion

    (Institut de Recherches Servier Oncology R&D Unit)

  • Gemma L. Kelly

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jia-Nan Gong

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Donia M. Moujalled

    (Australian Centre for Blood Diseases, Monash University)

  • Alain Bruno

    (Institut de Recherches Servier Oncology R&D Unit)

  • Márton Csekei

    (Servier Research Institute of Medicinal Chemistry)

  • Attila Paczal

    (Servier Research Institute of Medicinal Chemistry)

  • Zoltán B. Szabo

    (Servier Research Institute of Medicinal Chemistry)

  • Szabolcs Sipos

    (Servier Research Institute of Medicinal Chemistry)

  • Gábor Radics

    (Servier Research Institute of Medicinal Chemistry)

  • Agnes Proszenyak

    (Servier Research Institute of Medicinal Chemistry)

  • Balázs Balint

    (Servier Research Institute of Medicinal Chemistry)

  • Levente Ondi

    (Servier Research Institute of Medicinal Chemistry)

  • Gábor Blasko

    (Servier Research Institute of Medicinal Chemistry)

  • Alan Robertson

    (Vernalis (R&D) Ltd.)

  • Allan Surgenor

    (Vernalis (R&D) Ltd.)

  • Pawel Dokurno

    (Vernalis (R&D) Ltd.)

  • Ijen Chen

    (Vernalis (R&D) Ltd.)

  • Natalia Matassova

    (Vernalis (R&D) Ltd.)

  • Julia Smith

    (Vernalis (R&D) Ltd.)

  • Christopher Pedder

    (Vernalis (R&D) Ltd.)

  • Christopher Graham

    (Vernalis (R&D) Ltd.)

  • Aurélie Studeny

    (Institut de Recherches Servier Oncology R&D Unit)

  • Gaëlle Lysiak-Auvity

    (Institut de Recherches Servier Oncology R&D Unit)

  • Anne-Marie Girard

    (Institut de Recherches Servier Oncology R&D Unit)

  • Fabienne Gravé

    (Institut de Recherches Servier Oncology R&D Unit)

  • David Segal

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Chris D. Riffkin

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Giovanna Pomilio

    (Australian Centre for Blood Diseases, Monash University)

  • Laura C. A. Galbraith

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Brandon J. Aubrey

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    The Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre)

  • Margs S. Brennan

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Marco J. Herold

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Catherine Chang

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ghislaine Guasconi

    (Institut de Recherches Servier Oncology R&D Unit)

  • Nicolas Cauquil

    (Institut de Recherches Servier Oncology R&D Unit)

  • Fabien Melchiore

    (Institut de Recherches Servier)

  • Nolwen Guigal-Stephan

    (Institut de Recherches Servier)

  • Brian Lockhart

    (Institut de Recherches Servier)

  • Frédéric Colland

    (Institut de Recherches Servier Oncology R&D Unit)

  • John A. Hickman

    (Institut de Recherches Servier Oncology R&D Unit)

  • Andrew W. Roberts

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    The Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre
    Faculty of Medicine, The University of Melbourne)

  • David C. S. Huang

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andrew H. Wei

    (Australian Centre for Blood Diseases, Monash University
    The Alfred Hospital)

  • Andreas Strasser

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Guillaume Lessene

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    The University of Melbourne)

  • Olivier Geneste

    (Institut de Recherches Servier Oncology R&D Unit)

Abstract

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Suggested Citation

  • András Kotschy & Zoltán Szlavik & James Murray & James Davidson & Ana Leticia Maragno & Gaëtane Le Toumelin-Braizat & Maïa Chanrion & Gemma L. Kelly & Jia-Nan Gong & Donia M. Moujalled & Alain Bruno &, 2016. "The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models," Nature, Nature, vol. 538(7626), pages 477-482, October.
    • Handle: RePEc:nat:nature:v:538:y:2016:i:7626:d:10.1038_nature19830
    DOI: 10.1038/nature19830
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    Cited by:

    1. Martina Troiani & Manuel Colucci & Mariantonietta D’Ambrosio & Ilaria Guccini & Emiliano Pasquini & Angelica Varesi & Aurora Valdata & Simone Mosole & Ajinkya Revandkar & Giuseppe Attanasio & Andrea R, 2022. "Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Florian J. Bock & Egor Sedov & Elle Koren & Anna L. Koessinger & Catherine Cloix & Désirée Zerbst & Dimitris Athineos & Jayanthi Anand & Kirsteen J. Campbell & Karen Blyth & Yaron Fuchs & Stephen W. G, 2021. "Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Dongwen Lv & Pratik Pal & Xingui Liu & Yannan Jia & Dinesh Thummuri & Peiyi Zhang & Wanyi Hu & Jing Pei & Qi Zhang & Shuo Zhou & Sajid Khan & Xuan Zhang & Nan Hua & Qingping Yang & Sebastian Arango & , 2021. "Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Shamim Naghdi & Piyush Mishra & Soumya Sinha Roy & David Weaver & Ludivine Walter & Erika Davies & Anil Noronha Antony & Xuena Lin & Gisela Moehren & Mark A. Feitelson & Christopher A. Reed & Tullia L, 2025. "VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    5. Andrea Lopez & Denis E. Reyna & Nadege Gitego & Felix Kopp & Hua Zhou & Miguel A. Miranda-Roman & Lars Ulrik Nordstrøm & Swathi-Rao Narayanagari & Ping Chi & Eduardo Vilar & Aristotelis Tsirigos & Evr, 2022. "Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Yexuan Deng & Sarah T. Diepstraten & Margaret A. Potts & Göknur Giner & Stephanie Trezise & Ashley P. Ng & Gerry Healey & Serena R. Kane & Amali Cooray & Kira Behrens & Amy Heidersbach & Andrew J. Kue, 2022. "Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Chendi Li & Mohammed Usman Syed & Anahita Nimbalkar & Yi Shen & Melissa D. Vieira & Cameron Fraser & Zintis Inde & Xingping Qin & Jian Ouyang & Johannes Kreuzer & Sarah E. Clark & Grace Kelley & Emily, 2025. "LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    8. Jessica Ebner & Johannes Schmoellerl & Martin Piontek & Gabriele Manhart & Selina Troester & Bing Z. Carter & Heidi Neubauer & Richard Moriggl & Gergely Szakács & Johannes Zuber & Thomas Köcher & Mich, 2023. "ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Thomas Kimman & Marta Cuenca & Ralph G. Tieland & Dedeke Rockx-Brouwer & Jasmijn Janssen & Benjamin Motais & Anne Slomp & Corine Pleijte & Sabine Heijhuurs & Angelo D. Meringa & Wendy Boschloo & Douwe, 2025. "Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    10. Ella N. Hoogenboezem & Shrusti S. Patel & Justin H. Lo & Ashley B. Cavnar & Lauren M. Babb & Nora Francini & Eva F. Gbur & Prarthana Patil & Juan M. Colazo & Danielle L. Michell & Violeta M. Sanchez &, 2024. "Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    11. Jaskaren Kohli & Chen Ge & Eleni Fitsiou & Miriam Doepner & Simone M. Brandenburg & William J. Faller & Todd W. Ridky & Marco Demaria, 2022. "Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    12. Wei Jin & Yexuan Deng & John E. La Marca & Emily J. Lelliott & Sarah T. Diepstraten & Christina König & Lin Tai & Valentina Snetkova & Kristel M. Dorighi & Luke Hoberecht & Millicent G. Hedditch & Lau, 2025. "Advancing the genetic engineering toolbox by combining AsCas12a knock-in mice with ultra-compact screening," Nature Communications, Nature, vol. 16(1), pages 1-15, December.

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