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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We thank S. Courtade-Gaiani and D. Valour for bioinformatics support, E. Borges for assistance on manuscript formatting, E. Schneider and C. Wagner-Legrand, H. Johnson, G. Siciliano and K. Hughes for technical help for in vivo studies, N. Whitehead for protein production support, P. Bouillet and L. A. O’Reilly for assistance with histology, M. Fallowfield, J. D’Alessandro, L. Terry, V. Lemesre, J.-P. Galizzi and C. de la Moureyre for in vitro assay support, H. Simmonite for analytical support and L. Andrieu, L. Montane and A. Schmutz for biostatistical support. Research at WEHI is supported by the National Health and Medical Research Council Australia (NHMRC, GNT1016647, GNT1016701, GNT1020363, GNT1086291, GNT1049720, GNT1057742, GNT1079560), the Leukemia and Lymphoma Society (SCOR grant 7001-03), The Cancer Council (1086157 GLK, grant in aid to A.W.R. and D.C.S.H.), The Kay Kendall Leukemia Fund Intermediate Fellowship (KKL331 to G.L.K.), the Victoria Cancer Agency, the Australian Cancer Research Foundation, a Victorian State Government Operational Infrastructure Support (OIS) grant and the estate of Anthony (Toni) Redstone OAM.

Author information


  1. Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary

    • András Kotschy
    • , Zoltán Szlavik
    • , Márton Csekei
    • , Attila Paczal
    • , Zoltán B. Szabo
    • , Szabolcs Sipos
    • , Gábor Radics
    • , Agnes Proszenyak
    • , Balázs Balint
    • , Levente Ondi
    •  & Gábor Blasko
  2. Vernalis (R&D) Ltd., Cambridge CB21 6GB, UK

    • James Murray
    • , James Davidson
    • , Alan Robertson
    • , Allan Surgenor
    • , Pawel Dokurno
    • , Ijen Chen
    • , Natalia Matassova
    • , Julia Smith
    • , Christopher Pedder
    •  & Christopher Graham
  3. Institut de Recherches Servier Oncology R&D Unit, Croissy Sur Seine 78290, France

    • Ana Leticia Maragno
    • , Gaëtane Le Toumelin-Braizat
    • , Maïa Chanrion
    • , Alain Bruno
    • , Aurélie Studeny
    • , Gaëlle Lysiak-Auvity
    • , Anne-Marie Girard
    • , Fabienne Gravé
    • , Ghislaine Guasconi
    • , Nicolas Cauquil
    • , Frédéric Colland
    • , John A. Hickman
    •  & Olivier Geneste
  4. The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia

    • Gemma L. Kelly
    • , Jia-Nan Gong
    • , David Segal
    • , Chris D. Riffkin
    • , Laura C. A. Galbraith
    • , Brandon J. Aubrey
    • , Margs S. Brennan
    • , Marco J. Herold
    • , Catherine Chang
    • , Andrew W. Roberts
    • , David C. S. Huang
    • , Andreas Strasser
    •  & Guillaume Lessene
  5. Department of Medical Biology, University of Melbourne, Melbourne 3010, Australia

    • Gemma L. Kelly
    • , Jia-Nan Gong
    • , David Segal
    • , Chris D. Riffkin
    • , Laura C. A. Galbraith
    • , Brandon J. Aubrey
    • , Margs S. Brennan
    • , Marco J. Herold
    • , Catherine Chang
    • , Andrew W. Roberts
    • , David C. S. Huang
    • , Andreas Strasser
    •  & Guillaume Lessene
  6. Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia

    • Donia M. Moujalled
    • , Giovanna Pomilio
    •  & Andrew H. Wei
  7. Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Victorian Comprehensive Cancer Centre, Melbourne 3050, Australia

    • Brandon J. Aubrey
    •  & Andrew W. Roberts
  8. Institut de Recherches Servier, Biomarker Research Division, Croissy Sur Seine 78290, France.

    • Fabien Melchiore
    • , Nolwen Guigal-Stephan
    •  & Brian Lockhart
  9. Faculty of Medicine, The University of Melbourne, Melbourne 3010, Australia.

    • Andrew W. Roberts
  10. Department of Clinical Haematology, The Alfred Hospital, Melbourne 3004, Australia.

    • Andrew H. Wei
  11. Department of Pharmacology and Pharmaceutics, The University of Melbourne, Melbourne 3010, Australia

    • Guillaume Lessene


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A.K., Z.S., J.D., M.Cs., A.Pa., Z.B.S., S.S., G.R., A.Pr., B.B., L.O., G.B. and C.G. supervised and performed the chemistry. A.K., Z.B.S., J.M., J.D. and I.C. performed the drug design and molecular modelling. A.L.M., G.L.T.-B., G.L.K., J.-N.G., D.M.M., A.Stu., D.S., C.D.R., G.P., C.C., G.G. and N.C. performed cell based experiments. G.L.K., G.L.-A., A.-M.G., F.G., M.S.B., L.C.A.G. and M.J.H. performed the in vivo experiments. B.J.A. contributed to the histology analysis. J.M., A.R., A.Su., P.D., N.M., J.S. and C.P. produced recombinant proteins, performed biochemical assays and crystallographic studies. M.Ch., G.L.K., A.B. and M.J.H. designed the in vivo experiments. F.M., N.G.-S. and B.L. designed and performed the bioinformatic analysis. A.-L.M., J.M., J.D., G.L.K., F.C., J.A.H., A.W.R., D.C.S.H., A.H.W., A.Str., G.L. and O.G. supervised the studies, designed the experiments and interpreted the results. A.Str., G.L., D.C.S.H. and O.G. wrote the manuscript with the assistance of A.L.M., G.L.K. and the other authors.

Competing interests

G.L.T.-B., A.L.M., G.G., A.Stu., N.C., M.Ch., A.B., G.L.-A., A.-M.G., F.G., O.G., J.A.H., B.L., N.G.-S., F.C., F.M., A.K., Z.Szl., M.Cs., A.Pa., Z.Sza., S.S., G.R., L.O., A.Pr., B.B. and G.B. are employees of Servier. N.M., C.P., J.S., I.C., C.G., J.D., A.R., A.Su., P.D. and J.M. are employees of Vernalis (R&D) Ltd., G.L., A.Str., G.L.K., M.J.H., J.G., D.S., C.D.R., A.W.R., C.C., M.S.B. and D.C.S.H. are employees of the Walter and Eliza Hall Institute of Medical Research, which receives research funding and milestone payments in relation to venetoclax (ABT-199). G.L., A.Str., G.L.K., M.J.H., J.-N.G., D.S., C.D.R., A.W.R., M.S.B. and D.C.S.H. receive research funding from Servier. A.H.W. serves on the advisory board for Servier and receives research funding from Servier.

Corresponding author

Correspondence to Olivier Geneste.

Reviewer Information Nature thanks S. Fletcher, F. Stegmeier, G. Wagner and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Extended data figures

  1. 1.

    Biophysical characterization of the binding of MCL1 inhibitors to human and mouse MCL1 and serum effect on their cellular potency.

  2. 2.

    Targeting MCL1 genetically in H929 cells induces caspase-mediated cell death.

  3. 3.

    Impact of treatment with S63845 on the interaction of MCL1 with pro-apoptotic BCL-2 family members and on the level and stability of MCL1.

  4. 4.

    S63845 induces apoptosis of sensitive tumour derived cell lines.

  5. 5.

    Correlation between the sensitivity of multiple-myeloma-derived cell lines to S63845 and killing by the MCL1-selective ligand BIM2A. BAX/BAK dependency for S63845-induced killing in KMS-12-PE and AMO1 myeloma cells. Expression of pro-survival BCL-2 family proteins across a panel of multiple-myeloma-derived lines.

  6. 6.

    Anti-tumour efficacy and effect of dose scheduling of S63845 in H929 and AMO1 multiple myeloma xenograft models. The in vitro activity of S63845 in human Burkitt-lymphoma-derived cell lines and in vivo activity of S63845 on individual Eμ-Myc lymphoma cell lines.

  7. 7.

    Spearman correlations distribution in haematological cell lines and AML data on patient samples.

  8. 8.

    S63845 activity in solid tumour-derived cell lines, correlation with BCL-XL mRNA expression and impact of treatment with the MEK1/2 inhibitor, trametenib, the HER-2 inhibitor, lapatinib, the B-RAF inhibitor, PLX-4032, or the EGFR inhibitor, tarceva, on the levels of p-ERK and the pro-apoptotic protein BIM.

  9. 9.

    Tolerability of S63845 in mice and impact of treatment on healthy tissues at doses that prevent tumour expansion.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-2, Supplementary Tables 1-2 and Supplementary Methods.


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