Here, we describe an approach to identify novel selective estrogen receptor downregulator (SERD) compounds with improved properties such as oral bioavailability and the potential of increased efficacy compared to currently marketed drug treatments. Previously, methodologies such as Western blotting and transient cell reporter assays have been used to identify and characterize SERD compounds, but such approaches can be limited due to low throughput and sensitivity, respectively. We have used an endogenous cell-imaging strategy that has both the throughput and sensitivity to support a large-scale hit-to-lead program to identify novel compounds. A screening cascade with a suite of assays has been developed to characterize compounds that modulate estrogen receptor α (ERα)-mediated signaling or downregulate ERα levels in cells. Initially, from a focused high-throughput screening, novel ERα binders were identified that could be modified chemically into ERα downregulators. Following this, cellular assays helped determine the mechanism of action of compounds to distinguish between on-target and off-target compounds and differentiate SERDs, selective estrogen receptor modulator (SERM) compounds, and agonist ERα ligands. Data are shown to exemplify the characterization of ERα-mediated signaling inhibitors using a selection of literature compounds and illustrate how this cascade has been used to drive the chemical design of novel SERD compounds.
By Karen Jones|2022-05-12T14:23:13+01:00December 1st, 2015|Publications|Comments Off on A Screening Assay Cascade to Identify and Characterize Novel Selective Estrogen Receptor Downregulators (SERD’s).
Dr Karen Jones PhD. Karen is a Senior Research Scientist with over 10 years of experience in the pharmaceutical industry within the early drug discovery setting. Karen’s area of expertise is in the development of Ion Channel and GPCR assays which are used for compound screening in various formats from small scale bespoke experiments up to large scale fully automated screens. Karen is skilled at problem solving and has a proven track record of delivery with difficult targets leading to publications in peer reviewed journals.