Fatty Acid Mimetic Fragments as Liver Receptor Homologue-1 Modulators.

Area of Science:

• Molecular biology
• Endocrinology
• Drug discovery

Background:

• Liver receptor homologue-1 (LRH-1) is a transcription factor crucial for regulating genes involved in cholesterol and glucose metabolism, inflammation, and endoplasmic reticulum stress.
• LRH-1 is primarily expressed in the liver, intestine, and pancreas, making it a significant target for metabolic diseases and inflammatory conditions.
• Existing LRH-1 modulators are scarce, despite its therapeutic potential in metabolic disorders, inflammation, and even contraception.

Purpose of the Study:

• To explore fatty acid mimetics as potential modulators of LRH-1, leveraging its known phospholipid-binding properties.
• To discover novel ligand chemotypes for LRH-1 through focused fragment screening.
• To identify promising lead compounds for LRH-1 agonist development.

Main Methods:

• Focused fragment screening was employed to identify potential LRH-1 modulators.
• Structure-activity relationship (SAR) elucidation was performed on identified fragments.
• Orthogonal activity validation and target engagement studies were conducted to confirm modulatory effects.

Main Results:

• New ligand chemotypes targeting LRH-1 were discovered through fragment screening.
• Preliminary SAR studies provided initial insights into the structure-activity relationships of the identified compounds.
• Two fragment-like leads demonstrating promising activity were highlighted for further development as LRH-1 agonists.

Conclusions:

• Fatty acid mimetics represent a viable strategy for discovering LRH-1 modulators.
• The identified fragment-like leads warrant further investigation for the development of novel LRH-1 agonists.
• This research opens new avenues for therapeutic interventions targeting metabolic and inflammatory diseases via LRH-1 modulation.