The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
Journal Title
Nature
Publication Type
Journal Article
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.
Publisher
Springer Nature
WEHI Research Division(s)
Chemical Biology; Molecular Genetics Of Cancer; Cancer And Haematology
PubMed ID
27760111
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-10-25 02:58:27
Last Modified: 2018-03-26 02:58:22
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