Indeed, there are also INCB18424 941678-49-5 reports that channels including hERG have activities in addition to ion conductance, indicating that independent molecular targets might converge on common signaling pathways or processes also modulated by hERG and leading to the observed correlation. For example, there is a tendency that hERG inhibitors or LQT-causing drugs are also antagonists of the multidrug resistance U0126 MEK inhibitor transporter. Alternatively, hERG may be co-expressed with other channels correlated with oncogenesis which possess similar pharmacological profiles, such as hEAG, thus confounding causal inference of the relationship between hERG activity and gene expression response. We also note that the presence of inhibitors in the CMap outside the enriched clusters highlighted in our analysis indicates that this ��hERG signature�� is not necessarily ��dominant�� over other expression pattern, implying that other such patterns might perturb or mask the signature from being identified for some compounds. In this interpretation, the subset of clustered inhibitors highlighted in our analysis represent drugs for which this signature is dominant over or of equal strength with other expression responses of the compounds. Additionally, we note that a large portion of the compounds in this dataset exhibit silent or weak transcriptional response which prevents profiling for hERG inhibition using the proposed approach. As the signatures in CMap are uniformly generated at a 6 hour time point, it is possible that some compounds may display chronic transcriptional effects at a later time point, and thus be profiled by modifications in the original screening protocol. Indeed, previous studies of time course data from drug-induced gene expression responses have indicated that distinct expression patterns may be detected at different time points, even for frequent measurements such as 3, 6, and 9 hours. We thus hypothesize that some of the ��silent compounds�� in our study might have detectable signatures at later time points, while the hERG inhibitors outside of enriched clusters may exhibit a dominant ��hERG signature�� at earlier time points. Taken together, these results suggest that improved sensitivity for this assay might be achieved by using time course instead of single point expression data. Additionally, we note that the sensitivity of our assay may be effected by our choice of a 10 ��M IC50 threshold. While this threshold has been used in previous hERG predictive models, previous studies have also reported greater accuracy with a lower threshold.