Journal article

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

Mark F van Delft, Stephane Chappaz, Yelena Khakham, T Bui Chinh, 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 Show all

Nature Chemical Biology | NATURE PUBLISHING GROUP | Published : 2019

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..

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Grants

Awarded by Independent Research Institutes Infrastructure Support Scheme grant from the Australian National Health and Medical Research Council



Funding 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.