Figure 7
Assessing compound phenotypic activity through network perturbation analysis. (A). Characteristic connection curves of 39 kinases mapped to the interactome. 39 kinases were mapped to the interactome; collectively, they directly connect to 525 genes in the network. A network walking algorithm was developed to estimate the spread of the connectivity of each kinase by calculating the total number of nonredundant genes it connected at each step along the connection pathway. The smoothed connectivity curve of each of the 39 kinases was shown, with the maximum reaching 1040 for each kinase. Summation of connectivity for 39 kinases is represented by the broken line. (B). The chemical structure of LY2401401, a novel small molecule and a multi angiogenesis kinase inhibitor tested in the network perturbation experiment. (C). The connectivity index was calculated by an exponentially weighted sum of the connectivity at each stage of each kinase. The dose dependent network perturbation of each small molecule inhibitor was simulated as described in the methods section. The data were imported into Graphpad Prism software to estimate the EC50 values of network perturbation using Sigmoidal dose-response curve fitting. (D). Three small molecule kinase inhibitors were tested for cord formation. They all showed dose dependent inhibition of angiogenesis. Representative image summaries of the dose dependent responses are shown. The cord area data were imported to Graphpad Prism software, and normalized to the control group for EC50 calculation, using the same method as the one that was used to calculate the simulated network perturbation values. Shown in the figure are mean EC50s for each compound, averaged from two to four independent experiments.