Selective Glucocorticoid Receptor Modulation via Multiplexed Screening
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Solution Overview
Problem
Current glucocorticoid receptor (GR) therapies face challenges in achieving selective gene regulation, leading to both beneficial and harmful effects, with existing drugs causing debilitating side effects due to non-specific activation of GR signaling, and existing screening methods failing to predict GR gene regulation based on ligand design, limiting the identification of therapeutically relevant transcriptional selectivity.
Innovation Solution
A high-throughput, multiplexed system for measuring GR activity at multiple promoters simultaneously, allowing for the identification of selective GR modulators among natural products and FDA-approved compounds, which can activate or inhibit specific subsets of GR target genes, thereby facilitating the discovery of molecules that enhance beneficial effects while minimizing deleterious ones.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoid receptor (GR) therapies are administered to treat immune-mediated diseases, then beneficial anti-inflammatory effects are achieved, but severe dose-limiting side effects occur including osteoporosis, muscle wasting, and diabetes
Solution Approach 1:
The patent segments GR target genes into beneficial and harmful subsets, using selective modulators to activate only beneficial genes (e.g., anti-inflammatory genes) while leaving harmful genes (e.g., RANKL for bone resorption) unactivated. This selective gene-specific modulation resolves the contradiction by achieving therapeutic efficacy through beneficial gene activation while avoiding side effects from harmful gene activation.
Solution Approach 2:
The patent applies local quality by creating tissue-specific or promoter-specific GR modulation. Selective modulators are designed to affect GR activity in specific tissues or at specific gene promoters, allowing beneficial effects in target tissues while avoiding harmful effects in other tissues. This enables differentiated GR activity patterns across different biological contexts.
2Adaptability or versatility
If selective GR ligands are developed to induce a subset of GR activities, then transcriptional selectivity is achieved, but it remains uncertain whether new ligands can produce therapeutically relevant transcriptional selectivity
Solution Approach 1:
The patent employs high-throughput screening systems with multiple reporters that provide feedback on GR activity at different promoters. This allows iterative optimization of selective modulators to achieve desired transcriptional selectivity patterns. The screening system measures GR activity at multiple promoters simultaneously, enabling identification of compounds with specific transcriptional profiles that match therapeutic requirements.
Solution Approach 2:
The patent develops a universal high-throughput screening platform that can evaluate GR modulators across multiple promoters and cell types. This multi-functional system allows a single compound to be assessed for its ability to produce different transcriptional outcomes across multiple targets, facilitating the discovery of selective modulators with therapeutically relevant profiles.
3Productivity
If transcription based screens for novel GR modulators are conducted at a single experimental promoter, then screening efficiency is maintained, but efficient identification of molecules that produce promoter-specific responses is prevented
Solution Approach 1:
The patent merges multiple promoter-specific reporter assays into a single high-throughput screening platform. Multiple promoters are monitored simultaneously in the same cells using different fluorescent reporters, allowing identification of compounds with promoter-specific effects while maintaining screening efficiency. This combining approach enables comprehensive evaluation of transcriptional selectivity without sacrificing productivity.
Solution Approach 2:
The patent adds dimensional complexity by monitoring multiple promoters simultaneously rather than sequentially. Using different fluorescent proteins with distinct excitation/emission spectra allows multiplexed measurement of GR activity at multiple promoters in parallel, transforming a one-dimensional single-promoter assay into a multi-dimensional multi-promoter system that identifies promoter-specific responses.
Data Source
AI summary
The invention relates to assays to detect selective gene regulation by ligand dependent transcription factors. The invention also relates to selective modulators of the glucocortocoid receptor for treatment of inflammation and allergic and immune-mediated diseases.