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The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
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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“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.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [60]
In the citing paper
“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/).”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [118]
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Metadata
- 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
- Published
- 2016-10
- Volume
- 538
- Issue
- 7626
- Pages
- 477-482
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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