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Nature. 2016 Oct 27;538(7626):477-482. doi: 10.1038/nature19830. Epub 2016 Oct 19.

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

Author information

1
Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
2
Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
3
Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
4
The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.
5
Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
6
Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia.
7
Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre, Melbourne 3050, Australia.
8
Institut de Recherches Servier, Biomarker Research Division, Croissy Sur Seine 78290, France.
9
Faculty of Medicine, The University of Melbourne, Melbourne 3010, Australia.
10
Department of Clinical Haematology, The Alfred Hospital, Melbourne 3004, Australia.
11
Department of Pharmacology and Pharmaceutics, The University of Melbourne, Melbourne 3010, Australia.

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.

PMID:
27760111
DOI:
10.1038/nature19830
[Indexed for MEDLINE]

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