Fragment-Based Discovery of Drug-like LRH-1 Agonists

Area of Science:

• Molecular Endocrinology
• Drug Discovery
• Metabolic Diseases

Background:

• Liver receptor homologue 1 (LRH-1) is a key transcription factor regulating metabolic balance and inflammation.
• LRH-1 is a promising therapeutic target for metabolic dysfunction, fatty liver disease, and cancer.
• Existing LRH-1 modulators possess limited drug-like properties, hindering therapeutic development.

Purpose of the Study:

• To discover and optimize novel LRH-1 ligands with enhanced physicochemical properties.
• To develop potent LRH-1 agonists for potential therapeutic applications.
• To investigate the functional effects of novel LRH-1 agonists in cellular models.

Main Methods:

• Fragment-based drug discovery approach to identify initial LRH-1 ligands.
• Lead optimization of a venlafaxine-related compound for LRH-1 activation.
• Structure-activity relationship studies to guide systematic structural variations.
• Validation of direct and cellular target engagement of novel agonists.
• Assessment of anti-inflammatory and ER-stress resolving properties in cellular assays.

Main Results:

• Identification of novel LRH-1 ligands with improved physicochemical characteristics.
• Development of a new LRH-1 agonist scaffold with high activation efficacy.
• Demonstrated direct and cellular target engagement of the optimized compounds.
• Validated anti-inflammatory and endoplasmic reticulum (ER) stress-resolving activities in cellular settings.

Conclusions:

• Novel LRH-1 agonists have been successfully developed through systematic optimization.
• These compounds exhibit potent activation efficacy and desirable functional properties.
• The discovered LRH-1 agonists represent promising therapeutic candidates for inflammatory and metabolic disorders.