Development of HTS assays to discover modulators of LRH-1

Scripps Research Institute, The, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): This proposal is in response to PA-07-320 titled "Development of Assays for High-Throughput Drug Screening." Our overall goal is to develop novel HTS-ready (high throughput screening-ready) assays suitable for rapid identification of small molecules that positively modulate (agonize) or negatively modulate (inverse agonize) the activity of the orphan nuclear receptor and transcription factor LRH-1 (liver receptor homolog-1). Modulation of LRH-1 target genes has been implicated in breast cancer and cholesterol homeostasis. Unfortunately, there are few reports of small molecule LRH-1 agonists and none of those reported are functionally selective, potent in cell based assays, and to date there are no reports of inverse agonists for LRH- 1. Thus, the discovery of potent and selective LRH-1 modulators remains critical to elucidate the function of LRH-1 in mammalian physiology and its role in various disease states. To help facilitate discovery and optimization of probe molecules we propose to develop the necessary assays to support a HTS campaign to discovery potent and selective LRH-1 receptor agonists and inverse agonists. Specifically we will aim to develop the following: 1) one primary assays, two counter-screens, and one cell viability assay;2) two cell- based functional assays;and 3) assays for selectivity profiling of modulators that emerge from HTS. Achievement of these three aims will provide a novel and innovative approach to support HTS and subsequent hit validation and probe optimization. Once developed and validated, these assays will be transferred to a MLPCN screening center. The outcome of this project will be new chemical probes that will help provide insight into this important target for intervention of cancer and cardiovascular disease. PUBLIC HEALTH RELEVANCE: Our overall goal of this proposal is to develop HTS-ready (high throughput screening-ready) assays suitable for rapid identification of small molecules that positively modulate (agonize) or negatively modulate (inverse agonize) the activity of the orphan nuclear receptor LRH-1 (liver receptor homolog-1). Target genes modulated by LRH-1 have been implicated in breast cancer and cholesterol homeostasis. The discovery of potent and functionally selective LRH-1 modulators is critical to elucidate the function of LRH-1 in mammalian physiology and its role in relevant disease states. To help facilitate discovery and optimization of probe molecules we propose to develop assays that are necessary to support a HTS campaign on this important protein.