Author: Heering, Jan ; Busch, Romy ; Marschner, Julian A. ; Lang, Alisa ; Schubert-Zsilavecz, Manfred ; Lillich, Felix F. ; Merk, Daniel ; Kaiser, Astrid ; Ildefeld, Niklas ; Proschak, Ewgenij

The phospholipid sensing transcription factor liver receptor homologue 1 (LRH-1) participates in the transcriptional regulation of metabolic balance and inflammation in liver, pancreas, and other tissues. It is an emerging target for metabolic dysfunction, fatty liver disease, and cancer, but LRH-1 modulators are rare and lack drug-like properties. We discovered new LRH-1 ligands with improved physicochemical features in a fragment-based approach and optimized a venlafaxine-related lead for LRH-1 activation. Despite a strict structure-activity relationship, systematic structural variation resulted in a new LRH-1 agonist scaffold with strong activation efficacy, validated direct and cellular target engagement, and anti-inflammatory and ER-stress-resolving properties in functional cellular settings.

14 Mar 2025·ACS Pharmacology & Translational Science

Fatty Acid Mimetic Fragments as Liver Receptor Homologue-1 Modulators

Article

Author: Proschak, Ewgenij ; Heitel, Pascal ; Lang, Alisa ; Isigkeit, Laura ; Stiller, Tanja ; Merk, Daniel ; Heering, Jan ; Ildefeld, Niklas ; Schubert-Zsilavecz, Manfred

The phospholipid-sensing transcription factor liver receptor homologue-1 (LRH-1) is mainly found in the liver, intestine, and pancreas where it participates in the transcriptional regulation of genes involved in cholesterol and glucose metabolism, inflammation, and endoplasmic reticulum stress. It holds promise as a target in metabolic disease and hepatic/intestinal inflammation treatment, and preliminary evidence suggests potential of LRH-1 modulation for contraception, but LRH-1 modulators are very rare. Based on phospholipid binding to LRH-1, we hypothesized potential for fatty acid mimetics as LRH-1 modulators and discovered new ligand chemotypes by focused fragment screening. Preliminary SAR elucidation, orthogonal activity validation, and target engagement studies highlighted two fragment-like leads for LRH-1 agonist development.

01 Jul 2022·Cell Chemical BiologyQ1 · BIOLOGY

A phospholipid mimetic targeting LRH-1 ameliorates colitis

Q1 · BIOLOGY

Article

Author: Patel, Anamika ; Cornelison, Jeffery L ; Melchers, Diana ; Calvert, John W ; Millings, Elizabeth J ; Flynn, Autumn R ; D'Agostino, Emma H ; Cato, Michael L ; Okafor, C Denise ; Moore, David D ; Liu, Xu ; Huang, Xiangsheng ; Houtman, René ; Mays, Suzanne G ; Ortlund, Eric A ; Wang, Guohui ; Jui, Nathan T

Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. We show that the phospholipid-mimicking groups interact with the targeted residues in crystal structures and improve binding affinity, LRH-1 transcriptional activity, and conformational changes at a key allosteric site. The best phospholipid mimetic markedly improves colonic histopathology and disease-related weight loss in a murine T cell transfer model of colitis. This evidence of in vivo efficacy for an LRH-1 modulator in colitis represents a leap forward in agonist development.

100 Deals associated with LRH-1 agonists(Johann Wolfgang Goethe-Universität Frankfurt am Main)

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Germany	Johann Wolfgang Goethe-Universität Frankfurt am Main	19 Mar 2025

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

LRH-1 agonists(Johann Wolfgang Goethe-Universität Frankfurt am Main)

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation