Thus it may also be possible to PF-04217903 improve the sensitivity of our method using inhibition measurements derived from higher drug concentrations. Research has also suggested that the duration of action potentials at 90% repolarization, a correlate of clinical LQT which is elongated by hERG inhibition, may be dependent upon multi-channel drugs effects, and thus the ability of our approach to forecast clinical endpoints may be aided by future integration of high-throughput recording data for other cardiac channels such as Nav1.5. Furthermore, despite the current lack of causal MK-2206 2HCl evidence linking the gene-expression profiles of the clustered hERG inhibitors in the CMap with functional modulation of the channel, this analysis does suggest an intriguing possibility that some hERG inhibitors induce a downstream signaling cascade as a consequence of current reduction that is visible as a global change in gene expression. Alternatively, these observations may indicate signaling pathways downstream of potassium channels that are not directly related to their role in conduction. A selection of these hypotheses is diagrammed in Figure 5. Certainly, profiling selective inhibitors of hERG such as E4031 which are not present in the CMap might help clarify these hypotheses, though the large number of transcriptionally silent compounds in the dataset suggests these selective inhibitors may not exhibit a detectable signature at 6 hour time points. From a practical standpoint, the observed similarity of microarray profiles among electrophysiologically confirmed but structurally diverse inhibitors argues for the potential of using such a surrogate as an informative descriptor for hERG liability complementing existing electrophysiological assays. The utility of such a platform is suggested by compounds such as the antidepressant Amoxapine which display slow on-rates beyond the temporal resolution of high throughput electrophysiological systems, and thus appear as ��negatives�� in our acute experimental electrophysiology data. In contrast, the microarray data utilized in this study were generated 6 hours following drug treatment, suggesting gene expression measurements may offer complementary temporal resolution not readily accessible by automated electrophysiology data, allowing high-throughput assessment of hERG inhibition in compounds with slow on-rates which have previously required manual patch clamp recordings to resolve. Furthermore, transcriptional signatures may identify false negatives from other assays, such as Sulconazole, which was labeled as inactive in ChemblDB from binding data.