PHOSPHO FLOW CYTOMETRY: SINGLE-CELL SIGNALING NETWORKS IN NEXT-GENERATION DRUG DISCOVERY AND PATIENT STRATIFICATION - Flow Cytometry in Drug Discovery and Development - page 310

FIGURE 15.6 Characterization of druggable signaling pathways and cell types. After
measuring the inhibitory effects of 8 compounds on 27 different cell type/signaling pathway
combinations, the resulting selectivity profiles were clustered to determine overall patterns of
selectivity or druggability. Cell type/pathway combinations that were inhibited at lower drug
concentrations (low IC 50 ) have high selectivity factors (yellow) and cluster together at the right
side of the dendrogram. As an example, the IL-6:pStat3 pathway in B cells was inhibited
strongly by the majority of the compounds tested and, therefore, is a druggable cell type/
pathway. Conversely, cell type/pathway combinations that were inhibited at high doses of drugs
(high IC 50 ) have low selectivity factors (cyan) and cluster to the left side of the dendrogram. The
IL-4:pStat6 pathway in CD4 þ T cells was particularly resistant to drug inhibition, making it a
poorly druggable cell type/pathway combination. Understanding of druggability of both cell
types and signaling pathways will enable more efficient choice of drug targets and ultimately
more successful drug discovery campaigns. (See the color version of the figure in the Color
Plates section.)
However, we did not observe a clear trend between the magnitude of signaling
induced and the druggability [16]. A larger panel of drugs must be tested to ensure that
these observations hold true; it may still turn out that signaling pathways that are not
fully activated by a particular ligand are more susceptible to inhibition.
Second, we observed that some cell types are more easily inhibited than others. For
instance, although IL-6 induced Stat3 phosphorylation at similar magnitudes in B
cells and CD4 þ and CD8 þ T cells, the B cells were consistently inhibited at 10-fold
lower doses than the two T cell populations [16]. The B cells appear to be more
“druggable” for IL-6 signaling, whereas T cells are more resilient. We believe that
these insights into how readily particular cell types are inhibited will greatly improve
drug discovery by guiding selection of potential drug targets in cell types that appear
amenable to treatment. For instance, research may show that a particular signaling
pathway is an ideal drug target for the treatment of autoimmune disease. However, if