2. Academic Validation
  3. Differential regulation of BAX and BAK apoptotic activity revealed by small molecules

Differential regulation of BAX and BAK apoptotic activity revealed by small molecules

  • Sci Adv. 2025 Mar 7;11(10):eadr8146. doi: 10.1126/sciadv.adr8146.
Kaiming Li 1 2,  Yu Q Yap 1 2,  Donia M Moujalled 1 2,  Fransisca Sumardy 1 2,  Yelena Khakham 1 2,  Angela Georgiou 1 2,  Michelle Jahja 1 2,  Thomas E Lew 1 2 3,  Melanie De Silva 1 2,  Meng-Xiao Luo 1 2,  Jia-Nan Gong 4,  Zheng Yuan 1 2,  Richard W Birkinshaw 1 2,  Peter E Czabotar 1 2,  Kym Lowes 1 2,  David C S Huang 1 2,  Benjamin T Kile 5,  Andrew H Wei 1 2 3,  Grant Dewson 1 2,  Mark F van Delft 1 2,  Guillaume Lessene 1 2 6
Affiliations

Affiliations

  • 1 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 2 Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • 3 Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
  • 4 National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for Animal Model, Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 5 Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
  • 6 Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
PMID: 40043112 DOI: 10.1126/sciadv.adr8146
Abstract

Defective Apoptosis mediated by B cell lymphoma 2 antagonist/killer (Bak) or B cell lymphoma 2-associated X protein (Bax) underlies various pathologies including autoimmune and degenerative conditions. On mitochondria, voltage-dependent anion channel 2 (VDAC2) interacts with Bak and Bax through a common interface to inhibit Bak or to facilitate Bax apoptotic activity. We identified a small molecule (WEHI-3773) that inhibits interaction between VDAC2 and Bak or Bax revealing contrasting effects on their apoptotic activity. WEHI-3773 inhibits Apoptosis mediated by Bax by blocking VDAC2-mediated Bax recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated Apoptosis by limiting inhibitory sequestration by VDAC2. In cells expressing both pro-apoptotic proteins, Apoptosis promotion by WEHI-3773 dominates, because activated Bak activates Bax through a feed-forward mechanism. Loss of Bax drives resistance to the Bcl-2 Inhibitor venetoclax in some leukemias. WEHI-3773 overcomes this resistance by promoting BAK-mediated killing. This work highlights the coordination of Bax and Bak apoptotic activity through interaction with VDAC2 that may be targeted therapeutically.

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