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

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, Márton Csekei, Attila Paczal, Zoltán B. Szabo, Szabolcs Sipos, Gábor Radics, Agnes Proszenyak, Balázs Balint, Levente Ondi, Gábor Blasko, Alan Robertson, Allan Surgenor, Pawel Dokurno, Ijen Chen, Natalia Matassova, Julia Smith, Christopher Pedder, Christopher Graham, Aurélie Studeny, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Gravé, David Segal, Chris D. Riffkin, Giovanna Pomilio, Laura C. A. Galbraith, Brandon J. Aubrey, Margs S. Brennan, Marco J. Herold, Catherine Chang, Ghislaine Guasconi, Nicolas Cauquil, Fabien Melchiore, Nolwen Guigal-Stephan, Brian Lockhart, Frédéric Colland, John A. Hickman, Andrew W. Roberts, David C. S. Huang, Andrew H. Wei, Andreas Strasser, Guillaume Lessene and Olivier Geneste ()
Additional contact information
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
Jia-Nan Gong: The Walter and Eliza Hall Institute of Medical Research
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
Chris D. Riffkin: The Walter and Eliza Hall Institute of Medical Research
Giovanna Pomilio: Australian Centre for Blood Diseases, Monash University
Laura C. A. Galbraith: The Walter and Eliza Hall Institute of Medical Research
Brandon J. Aubrey: The Walter and Eliza Hall Institute of Medical Research
Margs S. Brennan: The Walter and Eliza Hall Institute of Medical Research
Marco J. Herold: The Walter and Eliza Hall Institute of Medical Research
Catherine Chang: The Walter and Eliza Hall Institute of Medical Research
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
David C. S. Huang: The Walter and Eliza Hall Institute of Medical Research
Andrew H. Wei: Australian Centre for Blood Diseases, Monash University
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research
Guillaume Lessene: The Walter and Eliza Hall Institute of Medical Research
Olivier Geneste: Institut de Recherches Servier Oncology R&D Unit

Nature, 2016, vol. 538, issue 7626, 477-482

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19830

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