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 Bernard; Laure 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

doi:10.1038/s41589-019-0365-8

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 journal › Article › Research › peer-review

37 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1057-1066
Number of pages	10
Journal	Nature Chemical Biology
Volume	15
Issue number	11
DOIs	https://doi.org/10.1038/s41589-019-0365-8
Publication status	Published - 1 Nov 2019

Keywords

cell death
screening
small molecules
target validation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41589-019-0365-8

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

@article{2a5fece378ed42ddbc6b780a28d1272a,

title = "A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis",

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",

author = "\{van Delft\}, \{Mark F.\} and Stephane Chappaz and Yelena Khakham and Bui, \{Chinh T.\} and Debrincat, \{Marlyse A.\} and Lowes, \{Kym N.\} and Brouwer, \{Jason M.\} and Christoph Grohmann and Sharp, \{Phillip P.\} and Dagley, \{Laura F.\} and Lucy Li and Kate McArthur and Luo, \{Meng Xiao\} and Chin, \{Hui San\} and Fairlie, \{W. Douglas\} and Lee, \{Erinna F.\} and David Segal and Stephane Duflocq and Romina Lessene and Sabrina Bernard and Laure Peilleron and Thao Nguyen and Caroline Miles and Wan, \{Soo San\} and Lane, \{Rachael M.\} and Ahmad Wardak and Kurt Lackovic and Colman, \{Peter M.\} and Sandow, \{Jarrod J.\} and Webb, \{Andrew I.\} and Czabotar, \{Peter E.\} and Grant Dewson and Watson, \{Keith G.\} and Huang, \{David C.S.\} and Guillaume Lessene and Kile, \{Benjamin T.\}",

year = "2019",

month = nov,

day = "1",

doi = "10.1038/s41589-019-0365-8",

language = "English",

volume = "15",

pages = "1057--1066",

journal = "Nature Chemical Biology",

issn = "1552-4450",

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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 2019, 'A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis', Nature Chemical Biology, vol. 15, no. 11, pp. 1057-1066. https://doi.org/10.1038/s41589-019-0365-8

TY - JOUR

T1 - A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis

AU - van Delft, Mark F.

AU - Chappaz, Stephane

AU - Khakham, Yelena

AU - Bui, Chinh T.

AU - Debrincat, Marlyse A.

AU - Lowes, Kym N.

AU - Brouwer, Jason M.

AU - Grohmann, Christoph

AU - Sharp, Phillip P.

AU - Dagley, Laura F.

AU - Li, Lucy

AU - McArthur, Kate

AU - Luo, Meng Xiao

AU - Chin, Hui San

AU - Fairlie, W. Douglas

AU - Lee, Erinna F.

AU - Segal, David

AU - Duflocq, Stephane

AU - Lessene, Romina

AU - Bernard, Sabrina

AU - Peilleron, Laure

AU - Nguyen, Thao

AU - Miles, Caroline

AU - Wan, Soo San

AU - Lane, Rachael M.

AU - Wardak, Ahmad

AU - Lackovic, Kurt

AU - Colman, Peter M.

AU - Sandow, Jarrod J.

AU - Webb, Andrew I.

AU - Czabotar, Peter E.

AU - Dewson, Grant

AU - Watson, Keith G.

AU - Huang, David C.S.

AU - Lessene, Guillaume

AU - Kile, Benjamin T.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

KW - cell death

KW - screening

KW - small molecules

KW - target validation

UR - https://www.scopus.com/pages/publications/85074111173

U2 - 10.1038/s41589-019-0365-8

DO - 10.1038/s41589-019-0365-8

M3 - Article

C2 - 31591564

AN - SCOPUS:85074111173

SN - 1552-4450

VL - 15

SP - 1057

EP - 1066

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 11

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Apoptosis and stem cells in cancer development and therapy

Molecular regulation of blood cell production and function

Australian Synchrotron

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Apoptosis and stem cells in cancer development and therapy

Molecular regulation of blood cell production and function

Equipment

Australian Synchrotron

Cite this