Edited by Linda SpremulliApoptosis is thought to play a critical role in several pathological processes, such as neurodegenerative diseases (i.e. Parkinson's and Alzheimer's diseases) and various cardiovascular diseases. Despite the fact that apoptotic mechanisms are well defined, there is still no substantial therapeutic strategy to stop or even slow this process. Thus, there is an unmet need for therapeutic agents that are able to block or slow apoptosis in neurodegenerative and cardiovascular diseases. The outer mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1) is a convergence point for a variety of cell survival and death signals, including apoptosis. Recently, we demonstrated that VDAC1 oligomerization is involved in mitochondrion-mediated apoptosis. Thus, VDAC1 oligomerization represents a prime target for agents designed to modulate apoptosis. Here, high-throughput compound screening and medicinal chemistry were employed to develop compounds that directly interact with VDAC1 and prevent VDAC1 oligomerization, concomitant with an inhibition of apoptosis as induced by various means and in various cell lines. The compounds protected against apoptosis-associated mitochondrial dysfunction, restoring dissipated mitochondrial membrane potential, and thus cell energy and metabolism, decreasing reactive oxidative species production, and preventing detachment of hexokinase bound to mitochondria and disruption of intracellular Ca 2؉ levels. Thus, this study describes novel drug candidates with a defined mechanism of action that involves inhibition of VDAC1 oligomerization, apoptosis, and mitochondrial dysfunction. The compounds VBIT-3 and VBIT-4 offer a therapeutic strategy for treating different diseases associated with enhanced apoptosis and point to VDAC1 as a promising target for therapeutic intervention.Mitochondria play crucial roles in cellular energy generation and metabolism, maintenance of the cell redox potential, calcium homeostasis, pH control and fatty acid oxidation, cell signaling, proliferation, differentiation, aging, and death (1). It is therefore not surprising that mitochondrial dysfunction is associated with various human diseases (1, 2).Located at the outer mitochondrial membrane (OMM), 2 the voltage-dependent anion channel (VDAC) serves as a mitochondrial gatekeeper. Three VDAC isoforms have been discovered (3), but only for VDAC1 is there a complete set of structural and functional information available. VDAC1 controls the metabolic and energy cross-talk between mitochondria and the rest of the cell, mediating the fluxes of ions, nucleotides, and other metabolites across the OMM (4 -7).