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

Li, K; Yap, YQ; Moujalled, DM; Sumardy, F; Khakham, Y; Georgiou, A; Jahja, M; Lew, TE; De Silva, M; Luo, MX; Gong, JN; Yuan, Z; Birkinshaw, RW; Czabotar, PE; Lowes, K; Huang, DCS; Kile, BT; Wei, AH; Dewson, G; van Delft, MF; Lessene, G

Author(s): Li, K; Yap, YQ; Moujalled, DM; Sumardy, F; Khakham, Y; Georgiou, A; Jahja, M; Lew, TE; De Silva, M; Luo, MX; Gong, JN; Yuan, Z; Birkinshaw, RW; Czabotar, PE; Lowes, K; Huang, DCS; Kile, BT; Wei, AH; Dewson, G; van Delft, MF; Lessene, G;
Details: Publication Year 2025-03-07,Volume 11,Issue #10,Page eadr8146
Journal Title: Science Advances
Publication Type: Research article
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.
Publisher: American Association for the Advancement of Science
Keywords: *bcl-2 Homologous Antagonist-Killer Protein/metabolism; *bcl-2-Associated X Protein/metabolism; *Apoptosis/drug effects; Humans; *Voltage-Dependent Anion Channel 2/metabolism; Mitochondria/metabolism/drug effects; Animals; Protein Binding; Mice; Cell Line, Tumor; Sulfonamides/pharmacology; Small Molecule Libraries/pharmacology
Department(s): Haematology
Publisher's Version: https://doi.org/10.1126/sciadv.adr8146
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.adr8146
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-08 06:06:15

Last Modified: 2025-04-08 06:21:00