Much of the past effort has focused on targeting caspases, proteases that mediate many of the hallmarks of apoptotic cell death. However, in mammalian cells, apoptotic caspases principally ensure the rapid clearance of dying cells and prevent damage-associated molecular pattern signaling. Mark F. van Delft , et al. set out to test the hypothesis that a more effective strategy to block apoptosis pharmacologically would be before caspase activation. The related proteins initiate apoptosis by inhibiting pro-survival proteins and activating BAX/BAK, resulting in mitochondrial outer membrane permeabilization (MOMP). MOMP permits the cytoplasmic efflux of cytochrome c, an event that leads to the apoptotic caspase cascade. In the absence of BAX and BAK, apoptotic cell death initiated via the intrinsic pathway is abolished.

VDAC2 has a pro-apoptotic role, owing to its involvement in the recruitment of Bak and GSK-3β to the OMM. In healthy, viable cells, Bak, primarily found in association with VDAC2, prevents its oligomerization, conferring anti-apoptotic properties to VDAC2. In cells undergoing apoptosis, Bak localization in the OMM leads to conditions conducive for Bak oligomerization, and in conjunction with GSK-3β recruitment, apoptosis ensues. These observations suggest a critical role of VDAC2 in regulating apoptosis in normal healthy cells.

WEHI-9625, a VDAC2:BAK interaction enhancer, blocks mBAK-mediated apoptosis

In the study, scientists report the identification of a novel tricyclic sulfone small molecule series (WEHI-9625 and analogs) that can block intrinsic apoptosis and preserve the clonogenic potential of cells otherwise destined to die. WEHI-9625 is a first-in-class inhibitor of apoptosis with an EC50 of 69 nM. WEHI-9625 binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. It is completely inactive against both human BAK and the closely related apoptosis effector BAX.

In vitro, WEHI-9625 (0-10 µM; Mcl1−/−Bax−/− MEFs cells) treatment could prevent cell death mediated by BAK and potently inhibits BIM BH3-induced loss of mitochondrial membrane potential in Bax−/−, but not Bak−/−, cells. In vivo, it demonstrates that blocking apoptosis at an early stage was both advantageous and pharmacologically tractable.


van Delft MF, et al. A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis. Nat Chem Biol. 2019 Oct 7.