The cHTS platform is used to reliably identify and quantify synergies between two (or more) compounds. There are therefore a number of powerful ways that the information provided can inform drug discovery and development programs.
Due to issues with lack of efficacy or issues with toxicity, many drugs fail to reach market or, if they do, have less of an impact than initially hoped. In many cases, the value of these compounds can be improved through the use of a second compound so that the combined impact, at the right doses is greater than would be predicted through the application of these compounds based on their individual dynamics. Synergies also allow for lower doses to be used that may be more in line with concentrations that are clinically achievable. Also, lower doses potentially lower the risk of off-target effects and decease side effects.
Horizon CRx Synergy Example: PI3K x MEK inhibition:
SIngle agents: Growth inhibition
Two drugs that inhibit key targets in signalling pathways known to be important for tumor cell proliferation/survival were screened in combination using the dose matrix format. Neither class of drug has proven to be efficacious in a clinical setting when deployed as monotherapies, however, combination screening identified a set of doses (blue box) that are synergistic, leading to cytotoxicity.
Prediction of patient response
Even once synergies have been identified, not all patients will respond the same way. It is well understood that cancer in particular is a highly variable disease, and patients can respond to therapies in very different ways. Therefore it is important to evaluate synergies in a range of cell lines reflecting a broad variety of patient backgrounds in order to determine the degree of synergy and how broadly it will be seen, and to identify non-responders.
Synergy scores are a simple way to visualize the combined results of a single dose matrix, very helpful when a large number of matrices are being evaluated across a panel of cell lines. Thereafter, the dose matrix can be used to specifically focus on target-relevant or clinically-relevant synergies (boxed area) and based on this strategy, cell lines can be categorized as likely responders (synergy) or non-responders (no synergy).
PI3K x MEK inhibition: High Resolution Analysis of Combination Activity
Synergy was seen across all cell lines although the level varied significantly and two examples are highlighted.
Combination drug discovery
When one compound is in development, particularly for complex diseases, it is becoming increasingly worthwhile to look for combinations that can enhance your compound’s efficacy, and this can be done even when no likely partner drug has been identified. By screening your compound against a wide range of known and approved drugs (CombinatoRx has a compound library that includes approved and emerging drugs as well as a diverse collection of molecular probes that can be paired with your lead molecule), these synergistic effects can be identified. And by performing these studies in cell line panels, the breadth of this effect can clearly be seen.
CRx Platform Identifies Novel Synergy with PI3K Pathway Inhibitors
The cHTS platform was used to screen a customer’s lead compound in combination with 200 compounds in 20 cell lines. The study identified several PI3K and mTOR inhibitors that showed broad effects and strong synergies with the lead. Results are shown in heat map format as generated by the Chalice software.
Identification of antagonism
Not all drug interactions, when they occur, are synergistic. It can be equally important to identify whether there is antagonism with established drugs, particularly if those drugs are commonly co-prescribed.
Evaluation of single agent and combination data
A customer’s lead molecule was screened in combination with a library of >200 approved, emerging drugs and well defined molecular probes using an optimized dose matrix format. Instances were seen both of synergy and antagonism. Results are shown in heat map format as generated by the Chalice software.