Targeting the orphan nuclear receptor LRH-1 with small molecules

用小分子靶向孤儿核受体 LRH-1

基本信息

批准号：
10660545
负责人：
John Winter Calvert
金额：
$ 56.93万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660545
关键词：
Address Adipose tissue Affinity Agonist American Antidiabetic Drugs Atherosclerosis Award Behavior Bile Acids Binding Binding Sites Biological Biological Assay Biological Availability Biology CRISPR/Cas technology Cardiovascular Diseases Characteristics Charge Chemicals Chemistry Clinical Development Diabetes Mellitus Disease Dose Drug Kinetics Epidemic Exposure to Fatty Acids Fatty acid glycerol esters Gene Expression Generations Glucose Health Homeostasis Human Insulin Insulin Resistance Knowledge Lead Ligand Binding Ligands Lipids Liver Measures Metabolic Metabolic Diseases Metabolic Pathway Modeling Modification Monitor Mus Myocardial Infarction NR5A2 gene Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nuclear Orphan Receptor Obese Mice Obesity Oral cavity Overnutrition Overweight Pharmacodynamics Pharmacology Phospholipids Plasma Proteins Proteomics Research Risk Rodent Rodent Model Series Stroke Structure Structure-Activity Relationship Surface Testing Therapeutic Therapeutic Agents Tissues United States Work biophysical properties comorbidity design diet-induced obesity dietary efficacy evaluation fatty liver disease glucose metabolism glucose tolerance humanized mouse improved in vivo innovation insight insulin sensitivity lipid metabolism lipidomics lipophilicity liquid chromatography mass spectrometry liver function mRNA Expression mortality risk mouse model new therapeutic target non-alcoholic fatty liver disease novel pre-clinical preclinical study reverse cholesterol transport small molecule success tool transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY Obesity is a growing epidemic in the United States, leading to increases in cases of nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and type II diabetes. A common characteristic of these diseases is aberrant lipid and glucose metabolism. This proposal centers on the nuclear hormone receptor, Liver Receptor Homolog 1 (LRH-1), which acts as an important regulator of lipid metabolism, reverse cholesterol transport, glucose sensing, and homeostasis. As such, LRH-1 represents a novel therapeutic target for metabolic diseases. LRH-1 binds to phospholipids (PLs) and is activated by the unusual PL dilauroylphosphatidylcholine (DLPC) which shows potent anti-diabetic effects. The discovery that LRH-1 is regulated by PL ligands reveals an exciting potential to tune LRH-1 activity for the treatment of metabolic diseases. However, PLs are labile and not suitable for clinical use, necessitating the development of small molecule agonists. This has proved challenging thus far, since very few small molecules can displace endogenous lipids from the large, lipophilic binding pocket. Recent studies in our lab have characterized a class of small molecules that are capable of this feat. Using robust SAR and innovative chemistry, we have designed potent LRH-1 agonists that display biological activity. We have modified our most potent and efficacious agonists to improve their biophysical properties, making them suitable for in vivo studies. The advancement of LRH-1 agonists as therapeutics has also been hindered by the lack of appropriate rodent models to screen potential candidates due to small sequence differences in the binding pocket of rodent and human LRH-1. To overcome this barrier, we used a CRISPR-Cas9 strategy to humanize the mouse LRH-1 ligand binding pocket. This permits activation by synthetic agonists while minimizing changes to endogenous interaction surfaces. These leaps forward in lead compound development and mouse model generation, in combination with our deep knowledge of LRH-1 structure and function, create an ideal platform to develop candidate preclinical LRH-1 modulators for metabolic disease. Here, we have developed a strategy to define mechanisms of action, target engagement, pharmacology, and disease efficacy of our lead compounds. In aim 1, we generate compounds with improved biophysical properties that mimic PL-like activation. We will perform mechanistic characterization of these compounds to explore how contacting the PL-binding site with different polar moieties improves LRH-1 activation. In aim 2, we will examine the behavior of our lead compounds from an ADME perspective. The primary objective will be to establish tractability of the compounds using our humanized mice, so that pharmacokinetic relationships can be established. In aim 3, we will use our humanized mice and a model of diet-induced obesity to evaluate the in vivo efficacy of our lead LRH-1 compounds to improve glucose tolerance and insulin resistance.

项目概要肥胖在美国日益流行，导致非酒精性脂肪肝病例增加疾病（NAFLD）、心血管疾病和 II 型糖尿病。这些疾病的一个共同特点是脂质和葡萄糖代谢异常。该提案以核激素受体、肝脏受体为中心同源物 1 (LRH-1)，作为脂质代谢的重要调节剂，逆转胆固醇转运，葡萄糖感应和体内平衡。因此，LRH-1代表了代谢性疾病的一个新的治疗靶点。疾病。 LRH-1 与磷脂 (PL) 结合并被不寻常的 PL 二月桂酰磷脂酰胆碱激活（DLPC）显示出有效的抗糖尿病作用。 LRH-1 受 PL 配体调节的发现揭示了调节 LRH-1 活性以治疗代谢疾病的令人兴奋的潜力。然而，PL 是不稳定的且不适合临床使用，需要开发小分子激动剂。这已经证明了迄今为止具有挑战性，因为很少有小分子可以从大的亲脂性脂质中取代内源性脂质装订口袋。我们实验室最近的研究已经表征了一类能够做到这一点的小分子壮举。利用强大的 SAR 和创新化学，我们设计了有效的 LRH-1 激动剂，生物活性。我们修改了最有效的激动剂，以改善其生物物理学特性，使其适合体内研究。 LRH-1 激动剂作为治疗药物的进展由于尺寸较小，缺乏适当的啮齿动物模型来筛选潜在的候选者也受到阻碍。啮齿动物和人类 LRH-1 结合口袋的序列差异。为了克服这个障碍，我们使用了 CRISPR-Cas9 策略使小鼠 LRH-1 配体结合袋人源化。这允许通过以下方式激活合成激动剂，同时最大限度地减少内源相互作用表面的变化。这些领先地位的飞跃结合我们对 LRH-1 的深入了解，进行化合物开发和小鼠模型生成结构和功能，创建一个理想的平台来开发候选临床前 LRH-1 调节剂代谢性疾病。在这里，我们制定了一项战略来定义行动机制、目标参与、我们的先导化合物的药理学和疾病功效。在目标 1 中，我们生成具有改进的化合物模拟 PL 样激活的生物物理特性。我们将对这些进行机械表征化合物来探索 PL 结合位点与不同极性部分的接触如何改善 LRH-1 激活。在目标 2 中，我们将从 ADME 角度检查先导化合物的行为。这主要目标是使用我们的人源化小鼠确定化合物的易处理性，以便可以建立药代动力学关系。在目标 3 中，我们将使用我们的人源化小鼠和模型饮食诱导的肥胖，以评估我们的先导 LRH-1 化合物改善血糖的体内功效耐受性和胰岛素抵抗。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Rho-GEF PIX-1 directs assembly or stability of lateral attachment structures between muscle cells.

DOI：
10.1038/s41467-020-18852-4
发表时间：
2020-10-06
期刊：
Nature communications
影响因子：
16.6
作者：
Moody JC;Qadota H;Reedy AR;Okafor CD;Shanmugan N;Matsunaga Y;Christian CJ;Ortlund EA;Benian GM
通讯作者：
Benian GM

Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK.

DOI：
10.1016/j.yjmcc.2018.01.011
发表时间：
2018-03
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Shimizu Y;Polavarapu R;Eskla KL;Nicholson CK;Koczor CA;Wang R;Lewis W;Shiva S;Lefer DJ;Calvert JW
通讯作者：
Calvert JW

Structural insights into glucocorticoid receptor function.