基于片段的药物样LRH-1激动剂的发现

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-03-19 DOI:10.1021/acsmedchemlett.4c0060410.1021/acsmedchemlett.4c00604

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

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引用次数: 0

摘要

磷脂感应转录因子肝受体同源物1 （LRH-1）参与肝脏、胰腺等组织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新兴靶点，但LRH-1调节剂非常罕见，缺乏药物样特性。我们以片段为基础的方法发现了新的LRH-1配体，这些配体具有改进的物理化学特征，并优化了用于LRH-1激活的文拉法辛相关先导物。尽管存在严格的结构-活性关系，但系统的结构变化导致了一种新的LRH-1激动剂支架，具有很强的激活功效，可以直接与细胞靶点结合，并在功能细胞环境中具有抗炎和内质网应激解决特性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

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

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.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.