2. Academic Validation
  3. A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis

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

  • Nat Chem Biol. 2019 Nov;15(11):1057-1066. doi: 10.1038/s41589-019-0365-8.
Mark F van Delft 1 2,  Stephane Chappaz 3 4 5,  Yelena Khakham 3 4,  Chinh T Bui 3 4,  Marlyse A Debrincat 6 3,  Kym N Lowes 3 4 7,  Jason M Brouwer 3 8,  Christoph Grohmann 3 4,  Phillip P Sharp 3 4,  Laura F Dagley 3 7,  Lucy Li 3 4,  Kate McArthur 3 4 5,  Meng-Xiao Luo 3 4,  Hui San Chin 6 3,  W Douglas Fairlie 3 8 9 10,  Erinna F Lee 3 8 9 10,  David Segal 6 3,  Stephane Duflocq 3 4,  Romina Lessene 3 4,  Sabrina Bernard 3 4,  Laure Peilleron 3 4,  Thao Nguyen 3 4,  Caroline Miles 3 7,  Soo San Wan 3 7,  Rachael M Lane 3 4 5,  Ahmad Wardak 3 8,  Kurt Lackovic 3 7,  Peter M Colman 3 8,  Jarrod J Sandow 3 7,  Andrew I Webb 3 7,  Peter E Czabotar 3 8,  Grant Dewson 3 11,  Keith G Watson 3 4,  David C S Huang  # 6 3,  Guillaume Lessene  # 12 13 14,  Benjamin T Kile  # 3 4 5
Affiliations

Affiliations

  • 1 Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [email protected].
  • 2 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. [email protected].
  • 3 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
  • 4 ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 5 Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
  • 6 Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 7 Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 8 Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 9 La Trobe Institute for Molecular Science, Latrobe University, Bundoora, Victoria, Australia.
  • 10 Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.
  • 11 Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 12 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. [email protected].
  • 13 ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [email protected].
  • 14 Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia. [email protected].
  • # Contributed equally.
PMID: 31591564 DOI: 10.1038/s41589-019-0365-8
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.

Figures
Products