Novel Assays and Human Model Systems for Epigenetic Drug Discovery

Novel Assays and Human Model Systems for Epigenetic Drug Discovery
Version:
v1

File Name/Number:
SGC

Year:
2013

Epigenetics can be defined as inheritable alterations in gene expression that arise independently of DNA sequence changes. Despite its relative infancy, the emergence of druggable targets that impact epigenetic signaling has the potential to serve as a new and exciting strategy to the treatment of human diseases including cancer, autoimmune and metabolic diseases.
At DiscoveRx, we have developed a comprehensive suite of in vitro assays and human model systems that collectively enable a robust characterization of an inhibitor’s target profile and its associated effects on complex biological signaling networks. Here we describe assays that evaluate inhibitor potency and selectivity across the industry’s largest panel of bromodomain targets and a novel intracellular binding assay for the assessment of cellular potency. In addition to characterizing known epigenetic inhibitors, we evaluated mature inhibitors for other intracellular targets. Interestingly, several of these inhibitors were shown to be potently cross-reactive with bromodomains in vitro as well as in primary human cells and highlight the potential for unforeseen, high affinity synergistic inhibition of these important epigenetic regulators.
Finally, we have profiled a number of benchmark HDACi and BET family bromodomain inhibitors in our BioMAP® platform consisting of a range of primary human cells co-cultured to model the complex signals and phenotypic responses of human disease biology. HDACi and BET inhibitors generated unique phenotypic signatures for each target class when compared to profiles for over 3000 clinical, failed pharmaceutical or tool compounds in the BioMAP database...