Lang Alisa, Ildefeld Niklas, Lillich Felix F, Kaiser Astrid, Busch Romy, Marschner Julian A, Proschak Ewgenij, Heering Jan, Schubert-Zsilavecz Manfred, Merk Daniel
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany.
ACS Med Chem Lett. 2025 Mar 20;16(4):575-582. doi: 10.1021/acsmedchemlett.4c00604. eCollection 2025 Apr 10.
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.
磷脂感应转录因子肝受体同源物1（LRH-1）参与肝脏、胰腺及其他组织中代谢平衡和炎症的转录调控。它是代谢功能障碍、脂肪肝疾病和癌症的一个新兴靶点，但LRH-1调节剂很少见且缺乏类药物特性。我们通过基于片段的方法发现了具有改善理化特性的新型LRH-1配体，并优化了一种与文拉法辛相关的LRH-1激活先导化合物。尽管存在严格的构效关系，但系统的结构变异产生了一种新型LRH-1激动剂支架，具有强大的激活效力、经过验证的直接和细胞靶向结合，以及在功能性细胞环境中的抗炎和内质网应激缓解特性。
