Drug PD is not only dependent on potency, but on the interplay between the potency, PK and the biological system. Therefore, we use a QSP model to simulate the predicted PD of the generated compounds. To evaluate the influence of the different optimization scenarios on the eventual tumor inhibition effect, the properties of the generated compounds were used as input to a QSP model adapted from Voronova et al. This mice mechanistic model (Figure ) describes the influence of adenosine occupancy of the A 2A R on the immune system, represented by the immune activation rate and systemic antigen. The immune activation rate stimulates the production of and differentiation of precursor T-cells, which in turn can increase tumor cell death. The systemic antigen has a dual role where it increases the influx of precursor T-cells, but immunosuppressive cells as well. The model also includes the effect of a PD-L1 mAb, which has a synergistic effect with inhibition of the A 2A R. As the effect in this model is based on the total concentration of the inhibitor and not the unbound concentration, the scenarios with minimization/maximization of FU are not considered here.