Small-Molecule ROR Modulators for NASH Metabolic Control
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Solution Overview
Problem
Current treatments for liver diseases such as cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), hepatic ischemia reperfusion injury, and primary biliary cirrhosis (PBC) lack effective modulators targeting retinoic acid receptor-related orphan receptors (RORs) to manage metabolic disorders and associated conditions.
Innovation Solution
Development of small molecule modulators, including agonists, repressors, inverse agonists, and antagonists, targeting RORα, RORβ, or RORγ to modulate ROR activity, thereby regulating ROR target genes involved in metabolism and liver disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for liver diseases are used, then existing therapeutic options are available, but effective modulators targeting RORs to manage metabolic disorders are lacking
Solution Approach 1:
The invention segments the ROR receptor family into three distinct isoforms (RORα, RORβ, RORγ) and develops specific modulators for each, allowing targeted treatment of different metabolic disorders associated with each isoform's expression pattern and function
Solution Approach 2:
The patent introduces small molecule modulators as intermediaries that bind to ROR receptors to induce conformational changes, thereby recruiting co-activator or co-repressor proteins to regulate transcription of metabolic genes involved in liver disease pathogenesis
2Adaptability or versatility
If ROR modulators are developed to treat liver diseases, then new therapeutic options are available, but the complexity of nuclear receptor modulation increases
Solution Approach 1:
The invention utilizes parameter changes in the ligand-binding domain conformation upon modulator binding, which triggers a cascade of conformational changes leading to co-activator/co-repressor recruitment and transcriptional regulation, thereby simplifying the complex modulation mechanism into a controllable parameter-based system
Data Source
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AI summary
Compounds, compositions and methods for modulating retinoic acid receptor-like orphan receptors (ROR) and associated diseases. Methods for treatment or prophylaxis of metabolic disorders, liver disorders or diseases, including NASH, immune disorders, central nervous system disorders, or cancer are disclosed.