Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/121678
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Type: Journal article
Title: A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis
Author: 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.
Bernard, S.
et al.
Citation: Nature Chemical Biology, 2019; 15(11):1057-1066
Publisher: Springer Nature
Issue Date: 2019
ISSN: 1552-4450
1552-4469
Statement of
Responsibility: 
Mark F. van Delft, Stephane Chappaz, Yelena Khakham, Chinh T. Bui, Marlyse A. Debrincat, Kym N. Lowes ... Benjamin T. Kile ... et al.
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.
Keywords: Cell death; screening; small molecules; target validation
Rights: © 2019, Springer Nature.
DOI: 10.1038/s41589-019-0365-8
Grant ID: http://purl.org/au-research/grants/nhmrc/1083077
http://purl.org/au-research/grants/nhmrc/9000220
http://purl.org/au-research/grants/nhmrc/1016701
http://purl.org/au-research/grants/nhmrc/1078924
http://purl.org/au-research/grants/nhmrc/461221
http://purl.org/au-research/grants/nhmrc/1113133
http://purl.org/au-research/grants/nhmrc/1024620
http://purl.org/au-research/grants/nhmrc/1117089
http://purl.org/au-research/grants/nhmrc/1022618
http://purl.org/au-research/grants/nhmrc/GNT1158137
http://purl.org/au-research/grants/nhmrc/461219
http://purl.org/au-research/grants/nhmrc/1016647
http://purl.org/au-research/grants/nhmrc/1079700
http://purl.org/au-research/grants/nhmrc/1043149
http://purl.org/au-research/grants/nhmrc/1063008
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