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

van Delft, MF; Chappaz, S; Khakham, Y; Bui, CT; Debrincat, MA; Lowes, KN; Brouwer, JM; Grohmann, C; Sharp, PP; Dagley, LF; Li, L; McArthur, K; Luo, MX; Chin, HS; Fairlie, WD; Lee, EF; Segal, D; Duflocq, S; Lessene, R; Bernard, S; Peilleron, L; Nguyen, T; Miles, C; Wan, SS; Lane, RM; Wardak, A; Lackovic, K; Colman, PM; Sandow, JJ; Webb, AI; Czabotar, PE; Dewson, G; Watson, KG; Huang, DCS; Lessene, G; Kile, BT

Author(s): van Delft, MF; Chappaz, S; Khakham, Y; Bui, CT; Debrincat, MA; Lowes, KN; Brouwer, JM; Grohmann, C; Sharp, PP; Dagley, LF; Li, L; McArthur, K; Luo, MX; Chin, HS; Fairlie, WD; Lee, EF; Segal, D; Duflocq, S; Lessene, R; Bernard, S; Peilleron, L; Nguyen, T; Miles, C; Wan, SS; Lane, RM; Wardak, A; Lackovic, K; Colman, PM; Sandow, JJ; Webb, AI; Czabotar, PE; Dewson, G; Watson, KG; Huang, DCS; Lessene, G; Kile, BT;
Details: Publication Year 2019-11,Volume 15,Issue #11,Page 1057-1066
Journal Title: Nature Chemical Biology
Publication Type: Journal Article
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.
Publisher: Springer Nature
Research Division(s): Blood Cells And Blood Cancer; Chemical Biology; Advanced Technology And Biology; Structural Biology; Ubiquitin Signalling
PubMed ID: 31591564
Publisher's Version: https://doi.org/10.1038/s41589-019-0365-8
NHMRC Grants: NHMRC/1083077, NHMRC/9000220, NHMRC/1024620, NHMRC/461221, NHMRC/1016701, NHMRC/1113133, NHMRC/1022618, NHMRC/1078924, NHMRC/1117089,
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Creation Date: 2019-10-23 02:22:56

Last Modified: 2019-12-03 09:16:40