Figure 1.
Chemical proteomics without (A) and with (B) soluble drug competition.
(A) The drug (blue) bound to a matrix (grey) retains the drug targets (green) and secondary binders (orange). Most unspecific proteins (red) are washed of but some could stick to the matrix. The retained proteins are analyzed with MS/MS. (B) If the soluble drug is supplemented, it blocks the binding pocket of its target yielding a reduced amount of pulled-down proteins that are specific drug binders. Only sticky unspecific proteins and weak drug targets are retained.
Figure 2.
The perturbed functional network is a protein-protein interaction (blue edges) network.
This network includes the uniform functional sub-network (triangular nodes) which shares one biological function and all drug targets (grey nodes) interacting with it. Bafetinib (Bafe) can impact nodes (red border) in the uniform functional sub-networks in two ways: Either the drug inhibits directly a node in the uniform functional sub-network (1) or it modulates the function through peripherally interacting drug targets (2).
Figure 3.
Perturbed functional sub-network based on induction of apoptosis by intracellular signals.
In the protein-protein interaction (edges) network, the Bafetinib profile (grey nodes) perturbs the biological process (triangular nodes) which is pivotal in BCR-ABL dependent CML. The drug affinity (at) is indicated by the node size. Kinases in the target profile have a red label. Proteins of the uniform functional sub-network interacting with inhibited kinases are shown with a red node border. K562 cells contain ABL1 and its fusion protein BCR-ABL which is not found by the algorithm in this sub-network. However, ABL1 pulldown is hidden by BCR-ABL and hence missed as target. Western plots proved ABL1 as a competed target [33] and hence influences are indicated with thin red borders.
Figure 4.
The bafetinib targets (grey nodes) perturb EGFR signaling which suggests a new application in lung cancer.
The drug profile interferes with many nodes of the uniform function sub-network (triangular nodes). The drug affinity is indicated by the node size (a large node means high affinity). Kinases in the target profile have a red label. Proteins of the uniform functional sub-network interacting with inhibited kinases are shown with a red node border. EGFR expressing cells are not known to carry the fusion protein BCR-ABL which diminishes the influence of BCR-ABL on the network (dashed lines).
Table 1.
Significantly perturbed functional sub-networks named by their basic function.