WEHI-9625 is a tricyclic sulfone, 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. WEHI-9625 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: WEHI-9625 demonstrates that blocking apoptosis at an early stage was both advantageous and pharmacologically tractable.