Fig. 4: Synergistic interactions between BH3-mimetics can be computationally identified and then experimentally validated.

A (Left panel) Model simulation predicting synergy between BCL2 and MCL1 inhibition in U2932 cells (green curve). The model predicts a moderate response to BCL2 inhibition alone (black curve), no response to MCL1 inhibition alone (blue curve) but a greater than additive response when MCL1 and BCL2 inhibition is combined at equal levels. (Right panel) Experimental data validates the model prediction, demonstrating synergy between the BCL2-specific inhibitor, ABT-199, and the MCL1-specific inhibitor, AZD5991. The combination was tested at equimolar concentrations. B Complete dose–response matrices showing the impact on cell viability of all combinations of simulated inhibition strengths (left) and experimentally measured BH3-mimetic doses (right) for BCL2 inhibition (ABT-199) and MCL1 inhibition (AZD5991). Viability was calculated at 72 h for both computational models and experimental measurements. Summary synergy scores of the model simulation (left panel) and experimental data (right panel), calculated using SynergyFinder software⁵⁰.