| Literature DB >> 27760111 |
András Kotschy1, Zoltán Szlavik1, James Murray2, James Davidson2, Ana Leticia Maragno3, Gaëtane Le Toumelin-Braizat3, Maïa Chanrion3, Gemma L Kelly4,5, Jia-Nan Gong4,5, Donia M Moujalled6, Alain Bruno3, Márton Csekei1, Attila Paczal1, Zoltán B Szabo1, Szabolcs Sipos1, Gábor Radics1, Agnes Proszenyak1, Balázs Balint1, Levente Ondi1, Gábor Blasko1, Alan Robertson2, Allan Surgenor2, Pawel Dokurno2, Ijen Chen2, Natalia Matassova2, Julia Smith2, Christopher Pedder2, Christopher Graham2, Aurélie Studeny3, Gaëlle Lysiak-Auvity3, Anne-Marie Girard3, Fabienne Gravé3, David Segal4,5, Chris D Riffkin4,5, Giovanna Pomilio6, Laura C A Galbraith4,5, Brandon J Aubrey4,5,7, Margs S Brennan4,5, Marco J Herold4,5, Catherine Chang4,5, Ghislaine Guasconi3, Nicolas Cauquil3, Fabien Melchiore8, Nolwen Guigal-Stephan8, Brian Lockhart8, Frédéric Colland3, John A Hickman3, Andrew W Roberts4,5,7,9, David C S Huang4,5, Andrew H Wei6,10, Andreas Strasser4,5, Guillaume Lessene4,5,11, Olivier Geneste3.
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.Entities:
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Year: 2016 PMID： 27760111 DOI： 10.1038/nature19830
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962