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A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis

Nature Chemical Biology volume 15, pages 1057–1066 (2019)Cite this article

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Abstract

Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.

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Fig. 1: Identification and development of potent small molecule inhibitors of apoptosis.
Fig. 2: WEHI-9625 selectively inhibits apoptosis mediated by mouse BAK.
Fig. 3: WEHI-9625 blocks an early step in BAK activation and preserves long-term clonogenic survival.
Fig. 4: Unique structural features in two distinct regions of mouse BAK confer selectivity to WEHI-9625.
Fig. 5: The tricyclic sulfone series interacts with VDAC2 and requires VDAC2 to inhibit BAK-mediated cell death.
Fig. 6: The interaction between BAK and VDAC2 influences the ability of WEHI-9625 to inhibit BAK.

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Data availability

All data generated or analyzed during this study are available upon request. Raw data is available for Figs. 1–6. Bax knockout and Mcl1 floxed mouse strains are available from Jackson Laboratories. All other materials generated in the course of our study will be made available upon request from the authors.

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Acknowledgements

We thank R. Youle (National Institute of Neurological Disorders and Stroke, Bethesda, USA) for providing HCT116 cells, L. Whitehead (The Walter and Eliza Hall Institute, Melbourne, Australia) for assistance with image analysis and the many other colleagues who have shared reagents and contributed to discussions throughout this project. We are grateful for the outstanding animal husbandry provided by The Walter and Eliza Hall Institute Bioservices staff, and expert assistance from the Institute’s Flow Cytometry Facility. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron. Our work was supported by project grants (nos. 1083077 to G.L. and M.F.vD., 1078924 to G.D. and A.W., 1158137 to G.L., P.E.C. and M.F.vD.), program grants (nos. 461219 to B.T.K., 461221 to D.C.S.H. and P.M.C., 1016701 to D.C.S.H. and P.M.C., 1016647 to B.T.K., 1113133 to D.C.S.H., P.M.C. and G.L.), fellowships (nos. 1024620 to E.L., 1022618 to P.M.C., 1079700 to P.E.C., 1043149 to D.C.S.H., 1117089 to G.L. and 1063008 to B.T.K.) and an Independent Research Institutes Infrastructure Support Scheme grant (no. 9000220) from the Australian National Health and Medical Research Council; Additional funding was provided by MuriGen Therapeutics to B.T.K. and D.C.S.H.; by the HEARing CRC to B.T.K. and G.L.; by the DHB Foundation to B.T.K and G.L.; by the Brownless Trust to B.T.K. and G.L.; a fellowship from the Sylvia and Charles Viertel Foundation to B.T.K.; the Australian Cancer Research Fund and a Victorian State Government Operational Infrastructure support grant.

Author information

Author notes

  1. Stephane Chappaz, Kate McArthur, Rachael M. Lane & Benjamin T. Kile

    Present address: Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia

  2. W. Douglas Fairlie & Erinna F. Lee

    Present address: Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia

  3. These authors contributed equally: David C.S. Huang, Guillaume Lessene, Benjamin T. Kile.

Authors and Affiliations

  1. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Mark F. van Delft, Marlyse A. Debrincat, Hui San Chin, David Segal & David C. S. Huang

  2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia

    Mark F. van Delft, Stephane Chappaz, Yelena Khakham, Chinh T. Bui, Marlyse A. Debrincat, Kym N. Lowes, Jason M. Brouwer, Christoph Grohmann, Phillip P. Sharp, Laura F. Dagley, Lucy Li, Kate McArthur, Meng-Xiao Luo, Hui San Chin, W. Douglas Fairlie, Erinna F. Lee, David Segal, Stephane Duflocq, Romina Lessene, Sabrina Bernard, Laure Peilleron, Thao Nguyen, Caroline Miles, Soo San Wan, Rachael M. Lane, Ahmad Wardak, Kurt Lackovic, Peter M. Colman, Jarrod J. Sandow, Andrew I. Webb, Peter E. Czabotar, Grant Dewson, Keith G. Watson, David C. S. Huang, Guillaume Lessene & Benjamin T. Kile

  3. ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Stephane Chappaz, Yelena Khakham, Chinh T. Bui, Kym N. Lowes, Christoph Grohmann, Phillip P. Sharp, Lucy Li, Kate McArthur, Meng-Xiao Luo, Stephane Duflocq, Romina Lessene, Sabrina Bernard, Laure Peilleron, Thao Nguyen, Rachael M. Lane, Keith G. Watson, Guillaume Lessene & Benjamin T. Kile

  4. Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Kym N. Lowes, Laura F. Dagley, Caroline Miles, Soo San Wan, Kurt Lackovic, Jarrod J. Sandow & Andrew I. Webb

  5. Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Jason M. Brouwer, W. Douglas Fairlie, Erinna F. Lee, Ahmad Wardak, Peter M. Colman & Peter E. Czabotar

  6. La Trobe Institute for Molecular Science, Latrobe University, Bundoora, Victoria, Australia

    W. Douglas Fairlie & Erinna F. Lee

  7. Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Grant Dewson

  8. Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia

    Guillaume Lessene

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Contributions

B.T.K., D.C.S.H. initiated the project. B.T.K., D.C.S.H. M.F.v.D. and G.L. designed and coordinated the study. G.D., K.L., P.E.C., P.M.C. W.D.F., E.F.L. and K.G.W. advised on various aspects of the study. G.L. supervised the medicinal chemistry team. Y.K., C.T.B., C.G., P.P.S., S.D., R.L., S.B., L.P., T.N., K.G.W. and G.L. designed and/or prepared compounds. A.W. produced protein for structural biology studies. J.M.B, P.M.C. and P.E.C. performed structural biology studies. K.N.L., C.M., S.S.W. and K.L. designed and performed high-throughput screening and assay support. M.F.v.D., M.A.D, L.L. K.McA., M.-X.L, H.S.C., W.D.F., E.L., D.S. and G.D. performed cell and molecular biology experiments. S.C. and R.M.L. performed mouse ex vivo experiments. C.G. performed UV crosslinking experiments. L.F.D., J.J.S. and A.I.W. designed and performed proteomics analysis. B.T.K, G.L. and M.F.v.D wrote the manuscript with major input from D.C.S.H., G.D., K.L., P.E.C., P.M.C and K.G.W. as well as all other authors. B.T.K., D.C.S.H., G.L. and M.F.v.D. acquired funding for this study.

Corresponding authors

Correspondence to Mark F. van Delft or Guillaume Lessene.

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B.T.K. was a consultant to MuriGen Pty Ltd between 2006 and 2010.

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Supplementary information

Supplementary Information

Supplementary Figures 1–19 and Supplementary Tables 1–3.

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Supplementary Dataset 1

iBAQ intensities for proteins identified by compound 7 affinity purification.

Supplementary Dataset 2

iBAQ intensities for proteins identified by compound 8 photocrosslinking, biotinylation and streptavidin capture.

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van Delft, M.F., Chappaz, S., Khakham, Y. et al. A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis. Nat Chem Biol 15, 1057–1066 (2019). https://doi.org/10.1038/s41589-019-0365-8

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