title: The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.
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.
authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: András
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Zoltán
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authors.lastname: Szlavik
authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
authors.forename: James
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.initials: J
authors.lastname: Davidson
authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.initials: AL
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
authors.forename: Gaëtane
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authors.lastname: Le Toumelin-Braizat
authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Kelly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
authors.forename: Jia-Nan
authors.initials: JN
authors.lastname: Gong
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia.
authors.forename: Donia M
authors.initials: DM
authors.lastname: Moujalled
authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
authors.forename: Alain
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authors.lastname: Bruno
authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Márton
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authors.lastname: Csekei
authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Attila
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Zoltán B
authors.initials: ZB
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Szabolcs
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Agnes
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Balázs
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Levente
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authors.affiliation: Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
authors.forename: Gábor
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK.
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.lastname: Gravé
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Segal
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
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authors.initials: CD
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authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia.
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authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
authors.forename: Laura C A
authors.initials: LC
authors.lastname: Galbraith
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.|Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre, Melbourne 3050, Australia.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Aubrey
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
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authors.initials: MS
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authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
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authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.affiliation: Institut de Recherches Servier, Biomarker Research Division, Croissy Sur Seine 78290, France.
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authors.affiliation: Institut de Recherches Servier, Biomarker Research Division, Croissy Sur Seine 78290, France.
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.|Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre, Melbourne 3050, Australia.|Faculty of Medicine, The University of Melbourne, Melbourne 3010, Australia.
authors.forename: Andrew W
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authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
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authors.initials: DC
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authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia.|Department of Clinical Haematology, The Alfred Hospital, Melbourne 3004, Australia.
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authors.initials: AH
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authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.
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authors.lastname: Strasser
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia.|Department of Pharmacology and Pharmaceutics, The University of Melbourne, Melbourne 3010, Australia.
authors.forename: Guillaume
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authors.affiliation: Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France.
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mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011743:Pyrimidines; C000614727:S63845; D013876:Thiophenes; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein