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Kotschy, András; Szlavik, Zoltán; Murray, James; Davidson, James; Maragno, Ana Leticia; Le Toumelin-Braizat, Gaëtane; Chanrion, Maïa; Kelly, Gemma L; Gong, Jia-Nan; Moujalled, Donia M; Bruno, Alain; Csekei, Márton; Paczal, Attila; Szabo, Zoltán B; Sipos, Szabolcs; Radics, Gábor; Proszenyak, Agnes; Balint, Balázs; Ondi, Levente; Blasko, Gábor; Robertson, Alan; Surgenor, Allan; Dokurno, Pawel; Chen, Ijen; Matassova, Natalia; Smith, Julia; Pedder, Christopher; Graham, Christopher; Studeny, Aurélie; Lysiak-Auvity, Gaëlle; Girard, Anne-Marie; Gravé, Fabienne; Segal, David; Riffkin, Chris D; Pomilio, Giovanna; Galbraith, Laura C A; Aubrey, Brandon J; Brennan, Margs S; Herold, Marco J; Chang, Catherine; Guasconi, Ghislaine; Cauquil, Nicolas; Melchiore, Fabien; Guigal-Stephan, Nolwen; Lockhart, Brian; Colland, Frédéric; Hickman, John A; Roberts, Andrew W; Huang, David C S; Wei, Andrew H; Strasser, Andreas; Lessene, Guillaume; Geneste, Olivier
Nature (London), 10/2016, Letnik: 538, Številka: 7626Journal Article
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.
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