Download MendeleyThe MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.
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., Grave, F., Segal, D., Riffkin, C.D., Pomilio, G., Galbraith, L.C., 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., Wei, A.H., Strasser, A., Lessene, G., Geneste, O.(2016) Nature 538: 477-482
- PubMed: 27760111
- DOI: https://doi.org/10.1038/nature19830
- Primary Citation of Related Structures:
5LOF - PubMed 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.
Organizational Affiliation:
Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
