The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
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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