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

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dc.contributor.authorLi, K.
dc.contributor.authorYap, Y.Q.
dc.contributor.authorMoujalled, D.M.
dc.contributor.authorSumardy, F.
dc.contributor.authorKhakham, Y.
dc.contributor.authorGeorgiou, A.
dc.contributor.authorJahja, M.
dc.contributor.authorLew, T.E.
dc.contributor.authorDe Silva, M.
dc.contributor.authorLuo, M.X.
dc.contributor.authorGong, J.N.
dc.contributor.authorYuan, Z.
dc.contributor.authorBirkinshaw, R.W.
dc.contributor.authorCzabotar, P.E.
dc.contributor.authorLowes, K.
dc.contributor.authorHuang, D.C.S.
dc.contributor.authorKile, B.T.
dc.contributor.authorWei, A.H.
dc.contributor.authorDewson, G.
dc.contributor.authorvan Delft, M.F.
dc.contributor.authoret al.
dc.date.issued2025
dc.description.abstractDefective 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.
dc.description.statementofresponsibilityKaiming Li, Yu Q. Yap, Donia M. Moujalled, Fransisca Sumardy, Yelena Khakham, Angela Georgiou, Michelle Jahja, Thomas E. Lew, Melanie De Silva, Meng-Xiao Luo, Jia-nan Gong, Zheng Yuan, Richard W. Birkinshaw, Peter E. Czabotar, Kym Lowes, David C. S. Huang, Benjamin T. Kile, Andrew H. Wei, Grant Dewson, Mark F. van Delft, Guillaume Lessene
dc.identifier.citationScience Advances, 2025; 11(10):eadr8146-1-eadr8146-14
dc.identifier.doi10.1126/sciadv.adr8146
dc.identifier.issn2375-2548
dc.identifier.issn2375-2548
dc.identifier.orcidKile, B.T. [0000-0002-8836-8947]
dc.identifier.urihttps://hdl.handle.net/2440/146398
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1043149
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1156024
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2016894
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2009062
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1117089
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2018071
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2004446
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/158137
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1158137
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1158137
dc.rightsCopyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. Distributed under acreative commons Attribution NonCommercial License 4.0 (CC BY-NC).
dc.source.urihttps://doi.org/10.1126/sciadv.adr8146
dc.subjectapoptosis; mitochondria; apoptotic activity; BAX; BAK
dc.subject.meshCell Line, Tumor
dc.subject.meshMitochondria
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshApoptosis
dc.subject.meshProtein Binding
dc.subject.meshVoltage-Dependent Anion Channel 2
dc.subject.meshbcl-2 Homologous Antagonist-Killer Protein
dc.subject.meshbcl-2-Associated X Protein
dc.subject.meshSmall Molecule Libraries
dc.titleDifferential regulation of BAX and BAK apoptotic activity revealed by small molecules
dc.typeJournal article
pubs.publication-statusPublished

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