The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
- Author(s)
- Kotschy, A; Szlavik, Z; Murray, J; Davidson, J; Maragno, AL; Le Toumelin-Braizat, G; Chanrion, M; Kelly, GL; Gong, JN; Moujalled, DM; Bruno, A; Csekei, M; Paczal, A; Szabo, ZB; 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, AM; Grave, F; Segal, D; Riffkin, CD; Pomilio, G; Galbraith, LC; Aubrey, BJ; Brennan, MS; Herold, MJ; Chang, C; Guasconi, G; Cauquil, N; Melchiore, F; Guigal-Stephan, N; Lockhart, B; Colland, F; Hickman, JA; Roberts, AW; Huang, DC; Wei, AH; Strasser, A; Lessene, G; Geneste, O;
- 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
- Research Division(s)
- Chemical Biology; Molecular Genetics Of Cancer; Cancer And Haematology
- PubMed ID
- 27760111
- Publisher's Version
- https://doi.org/10.1038/nature19830
- NHMRC Grants
- NHMRC/1016647, NHMRC/1016701, NHMRC/1020363, NHMRC/1086291, NHMRC/1049720, NHMRC/1057742, NHMRC/1079560,
- Terms of Use/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