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

in Science advances by Kaiming 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

TLDR

  • A small molecule was identified that modulates the apoptotic activity of BAK and BAX by interacting with VDAC2, potentially leading to new therapeutic strategies.
  • WEHI-3773 promotes BAK-mediated apoptosis and overcomes resistance to venetoclax in leukemias with BAX deficiency.

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.

Overview

  • The study focuses on understanding the mechanism of defective apoptosis mediated by BAK and BAX proteins and identifying potential therapeutic targets.
  • The researchers describe a small molecule (WEHI-3773) that interacts with VDAC2 to modulate the apoptotic activity of BAK and BAX.
  • The primary objective of the study is to elucidate the role of VDAC2 in regulating the apoptotic activity of BAK and BAX and to identify potential therapeutic strategies for targeting this process.

Comparative Analysis & Findings

  • WEHI-3773 inhibits the interaction between VDAC2 and BAK, promoting BAK-mediated apoptosis, while inhibiting the interaction between VDAC2 and BAX, blocking BAX-mediated apoptosis.
  • In cells expressing both BAK and BAX, WEHI-3773 promotes apoptosis by activating BAK, which in turn activates BAX through a feed-forward mechanism.
  • WEHI-3773 overcomes resistance to venetoclax by promoting BAK-mediated killing in leukemias that have lost BAX expression.

Implications and Future Directions

  • The study highlights the importance of coordinating BAX and BAK apoptotic activity through interactions with VDAC2, which may be targeted therapeutically.
  • Future research should investigate the specificity and safety of WEHI-3773 and its potential use in combination with other therapies.
  • The study's findings may lead to the development of new therapeutic strategies for treating autoimmune and degenerative conditions, as well as leukemias with BAX deficiency.
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