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
  • 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.
PMID: 27760111 DOI: 10.1038/nature19830
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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