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

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 BernardLaure 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

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1057-1066
Number of pages10
JournalNature Chemical Biology
Issue number11
Publication statusPublished - 1 Nov 2019


  • cell death
  • screening
  • small molecules
  • target validation

Cite this

van Delft, M. F., Chappaz, S., Khakham, Y., Bui, C. T., Debrincat, M. A., Lowes, K. N., Brouwer, J. M., Grohmann, C., Sharp, P. P., Dagley, L. F., Li, L., McArthur, K., Luo, M. X., Chin, H. S., Fairlie, W. D., Lee, E. F., Segal, D., Duflocq, S., Lessene, R., ... Kile, B. T. (2019). A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis. Nature Chemical Biology, 15(11), 1057-1066. https://doi.org/10.1038/s41589-019-0365-8