Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/21893
Title: A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis.
Authors: van Delft, Mark F;Chappaz, Stephane;Khakham, Yelena;Bui, Chinh T;Debrincat, Marlyse A;Lowes, Kym N;Brouwer, Jason M;Grohmann, Christoph;Sharp, Phillip P;Dagley, Laura F;Li, Lucy;McArthur, Kate;Luo, Meng-Xiao;Chin, Hui San;Fairlie, W Douglas;Lee, Erinna F;Segal, David;Duflocq, Stephane;Lessene, Romina;Bernard, Sabrina;Peilleron, Laure;Nguyen, Thao;Miles, Caroline;Wan, Soo San;Lane, Rachael M;Wardak, Ahmad;Lackovic, Kurt;Colman, Peter M;Sandow, Jarrod J;Webb, Andrew I;Czabotar, Peter E;Dewson, Grant;Watson, Keith G;Huang, David C S;Lessene, Guillaume;Kile, Benjamin T
Affiliation: Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia
Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
La Trobe Institute for Molecular Science, Latrobe University, Bundoora, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Issue Date: 2019
EDate: 2019-10-07
Citation: Nature chemical biology 2019; 15(11): 1057-1066
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21893
DOI: 10.1038/s41589-019-0365-8
ORCID: 0000-0002-3866-4318
0000-0003-4171-3712
0000-0002-8838-4146
0000-0002-3073-1643
0000-0002-2594-496X
0000-0002-1193-8147
0000-0002-8836-8947
0000-0003-1255-9808
PubMed URL: 31591564
Type: Journal Article
Appears in Collections:Journal articles

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