1. Academic Validation
  2. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

  • Nature. 2016 Oct 27;538(7626):477-482. doi: 10.1038/nature19830.
András Kotschy 1 Zoltán Szlavik 1 James Murray 2 James Davidson 2 Ana Leticia Maragno 3 Gaëtane Le Toumelin-Braizat 3 Maïa Chanrion 3 Gemma L Kelly 4 5 Jia-Nan Gong 4 5 Donia M Moujalled 6 Alain Bruno 3 Márton Csekei 1 Attila Paczal 1 Zoltán B Szabo 1 Szabolcs Sipos 1 Gábor Radics 1 Agnes Proszenyak 1 Balázs Balint 1 Levente Ondi 1 Gábor Blasko 1 Alan Robertson 2 Allan Surgenor 2 Pawel Dokurno 2 Ijen Chen 2 Natalia Matassova 2 Julia Smith 2 Christopher Pedder 2 Christopher Graham 2 Aurélie Studeny 3 Gaëlle Lysiak-Auvity 3 Anne-Marie Girard 3 Fabienne Gravé 3 David Segal 4 5 Chris D Riffkin 4 5 Giovanna Pomilio 6 Laura C A Galbraith 4 5 Brandon J Aubrey 4 5 7 Margs S Brennan 4 5 Marco J Herold 4 5 Catherine Chang 4 5 Ghislaine Guasconi 3 Nicolas Cauquil 3 Fabien Melchiore 8 Nolwen Guigal-Stephan 8 Brian Lockhart 8 Frédéric Colland 3 John A Hickman 3 Andrew W Roberts 4 5 7 9 David C S Huang 4 5 Andrew H Wei 6 10 Andreas Strasser 4 5 Guillaume Lessene 4 5 11 Olivier Geneste 3
Affiliations

Affiliations

  • 1 Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
  • 2 Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
  • 3 Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
  • 4 The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.
  • 5 Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
  • 6 Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia.
  • 7 Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre, Melbourne 3050, Australia.
  • 8 Institut de Recherches Servier, Biomarker Research Division, Croissy Sur Seine 78290, France.
  • 9 Faculty of Medicine, The University of Melbourne, Melbourne 3010, Australia.
  • 10 Department of Clinical Haematology, The Alfred Hospital, Melbourne 3004, Australia.
  • 11 Department of Pharmacology and Pharmaceutics, The University of Melbourne, Melbourne 3010, Australia.
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.

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