Cited by 1,047Cell death mechanisms and regulationCancer-related Molecular PathwaysAcute Myeloid Leukemia Research

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

Kotschy, András, Szlavik, Zoltán, Murray, James, Davidson, James, Maragno, Ana Leticia, Le Toumelin-Braizat, Gaëtane, Chanrion, Maïa, Kelly, Gemma L., Gong, Jia-Nan, Moujalled, Donia M., Bruno, Alain, Csekei, Márton, Paczal, Attila, Szabo, Zoltán B., Sipos, Szabolcs, Radics, Gábor, Proszenyak, Agnes, Balint, Balázs, Ondi, Levente, Blasko, Gábor, Robertson, Alan, Surgenor, Allan, Dokurno, Pawel, Chen, Ijen, Matassova, Natalia, Smith, Julia, Pedder, Christopher, Graham, Christopher, Studeny, Aurélie, Lysiak-Auvity, Gaëlle, Girard, Anne-Marie, Gravé, Fabienne, Segal, David, Riffkin, Chris D., Pomilio, Giovanna, Galbraith, Laura C. A., Aubrey, Brandon J., Brennan, Margs S., Herold, Marco J., Chang, Catherine, Guasconi, Ghislaine, Cauquil, Nicolas, Melchiore, Fabien, Guigal-Stephan, Nolwen, Lockhart, Brian, Colland, Frédéric, Hickman, John A., Roberts, Andrew W., Huang, David C. S., Wei, Andrew H., Strasser, Andreas, Lessene, Guillaume, Geneste, Olivier·2016·Nature

DOI 10.1038/nature19830

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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.

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“MCL1 and BCL2L1, a pair of anti-apoptotic genes often upregulated in cancer, share a synthetic lethal relationship (Han et al., 2017; Najm et al., 2017) and each have targeted inhibitors (S63845, hereafter “MCL1-i”; A-1331852, hereafter “BCL2L1-i”) (Kotschy et al., 2016; Leverson et al., 2015).”
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Authors: Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A. L., Le Toumelin-Braizat, G., Chanrion, M., Kelly, G. L., Gong, J.-N., Moujalled, D. M., Bruno, A., Csekei, M., Paczal, A., Szabo, Z. B., Sipos, S., Radics, G., Proszenyak, A., Balint, B., Ondi, L., Blasko, G., Robertson, A., Surgenor, A., Dokurno, P., Chen, I., Matassova, N., Smith, J., Pedder, C., Graham, C., Studeny, A., Lysiak-Auvity, G., Girard, A.-M., Gravé, F., Segal, D., Riffkin, C. D., Pomilio, G., Galbraith, L. C. A., Aubrey, B. J., Brennan, M. S., Herold, M. J., Chang, C., Guasconi, G., Cauquil, N., Melchiore, F., Guigal-Stephan, N., Lockhart, B., Colland, F., Hickman, J. A., Roberts, A. W., Huang, D. C. S., Wei, A. H., Strasser, A., Lessene, G., & Geneste, O.
Affiliations: Vernalis (R&D) Limited (United Kingdom) (GB)
Institut de Recherches Internationales Servier (France) (FR)
The University of Melbourne (AU)
Monash University (AU)
The Royal Melbourne Hospital (AU)
The Alfred Hospital (AU)
Corresponding author: Geneste, Olivier
ORCID: Kotschy, András
Murray, James
Davidson, James
Kelly, Gemma L.
Moujalled, Donia M.
Surgenor, Allan
Dokurno, Pawel
Chen, Ijen
Matassova, Natalia
Graham, Christopher
Girard, Anne-Marie
Segal, David
Riffkin, Chris D.
Galbraith, Laura C. A.
Aubrey, Brandon J.
Brennan, Margs S.
Herold, Marco J.
Chang, Catherine
Melchiore, Fabien
Colland, Frédéric
Hickman, John A.
Roberts, Andrew W.
Huang, David C. S.
Wei, Andrew H.
Strasser, Andreas
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2016-10
Volume: 538
Issue: 7626
Pages: 477-482
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature19830
OpenAlex: W2534349779
Semantic Scholar: 804d41f048a7386a3e6b3fcd1589511de3fabcd4
Cited by: 1,047
References: 52
Citations by year: 2026: 63 · 2025: 87 · 2024: 75 · 2023: 100 · 2022: 99 · 2021: 133 · 2020: 152 · 2019: 123 · 2018: 120 · 2017: 83 · 2016: 8
FWCI: 48.12
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords: S63845, BH3-binding groove, apoptosis, mitochondrial apoptosis, multiple myeloma, leukemia, lymphoma, solid tumors, antitumour activity, drug safety, combination therapy
MeSH terms: Animals, Antineoplastic Agents, Female, Humans, Leukemia, Lymphoma, Male, Models, Biological, Models, Molecular, Multiple Myeloma, Neoplasms, Pyrimidines, Thiophenes, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice, Myeloid Cell Leukemia Sequence 1 Protein

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

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