Kotschy, A. et al. (2016) The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature, 538(7626), pp. 477-482. (doi: 10.1038/nature19830) (PMID:27760111)
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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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Galbraith, Dr Laura |
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., and Geneste, O. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Nature |
Publisher: | Nature Publishing Group |
ISSN: | 0028-0836 |
ISSN (Online): | 1476-4687 |
Published Online: | 19 October 2016 |
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