A Screening Assay Cascade to Identify and Characterize Novel Selective Estrogen Receptor Downregulators (SERD’s).

Abstract

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.

Read more here: R Callis, A Rabow, M Tonge, R Bradbury, M Challinor, K Roberts, K Jones and G Walker. A Screening Assay Cascade to Identify and Characterize Novel Selective Estrogen Receptor Downregulators (SERD’s). J Biomol Screen. 20(6) 748-59. 2015.

By |2018-07-05T13:35:31+00:00December 1st, 2015|Publications|Comments Off on A Screening Assay Cascade to Identify and Characterize Novel Selective Estrogen Receptor Downregulators (SERD’s).

About the Author:

Dr Karen Jones graduated from the University of Liverpool with a degree in Pharmacology. After researching the basis for naphthoquinone and biguanide synergy, Karen also gained her PhD from the University of Liverpool. Karen worked at Astra Zeneca for some 14 years, most recently as project lead for multiple high throughput screening campaigns supporting projects in a range of disease areas including Neuroscience, Oncology, Cardiovascular and Metabolic disease. Previously to this Karen delivered high quality data from multiple in vitro assay formats, developed ion channel assays used to screen multiple ion channel targets, always improving procedures where possible and driving forward projects by focusing on quality and robustness.