The vast majority of drug candidates fail to reach the market because of toxicity or lack of efficacy. SuRE™ reporter libraries are used to monitor multiple pathways during initial compound screens and thereby enable early disqualification of potential drug targets based on off-target effects.
Parallel monitoring of multiple pathways during compound screens
Compound screens are typically performed based on a single read-out platform, for example a cell line that will produce a fluorescent protein under the control of an inflammation inducible gene promoter. Using such a platform, thousands of compounds can be tested for their effect on inflammation in a highly effective manner. However, in reality such screens are monitoring the effect of compounds on one specific gene promoter which is thought to represent the activity of an entire pathway (inflammation in this example) while ignoring the potential effect of the compounds on potential off-target pathways. Using dedicated SuRE™ reporter libraries we enable the monitoring of multiple promoters that serve as ‘sensors’ of the pathway of interests, while in parallel monitoring potential off-target pathways. We believe this will allow for early disqualification of compounds with off-target activity.
The construction of such a customary SuRE™ reporter library is performed in 2 steps. First, in the cell line of choice a genome-wide screen is performed to identify promoters that can serve as bona-fide ’sensors’ of the activity of the pathway of interest as well as for the activity of potential off-target pathways. Then, based on this screen, a dedicated SuRE™ reporter library containing these sensors is constructed which can then be used during compound screens.