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

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. +45 more·2016·Nature

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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Crossref · 10.1038/nature19830

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  • Sensitivity of cancer cells to MCL-1 inhibition is inversely related to BCL-XL expression level and the capacity for BCL-XL to neutralize pro-apoptotic BH3 proteins such as BIM.

    “Prior studies have demonstrated that sensitivity of cancer cells to MCL-1 inhibition is inversely related to BCL-XL expression level and the capacity for BCL-XL to neutralize pro-apoptotic BH3 proteins such as BIM60,61.”
  • Venetoclax is available for CLL patients failing conventional therapies; several similar molecules are in clinical development.

    “Conversely, the BCL2 inhibitor venetoclax is currently available for the treatment of CLL patients who fail to obtain clinical benefit from conventional therapies [1046], and several other molecules with a similar mechanism of action are currently in clinical development [118] (source https://clinicaltrials.gov/).”

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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
Venue
Nature
Published
2016-10
Volume
538
Issue
7626
Pages
477-482
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2534349779
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
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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