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.

项目摘要肥胖是美国的流行病，导致非酒精性脂肪肝脏的增加疾病（NAFLD），心血管疾病和II型糖尿病。这些疾病的共同特征是异常脂质和葡萄糖代谢。该建议集中于核激素受体，肝受体同源1（LRH-1），它是脂质代谢的重要调节剂，反向胆固醇转运，葡萄糖感应和稳态。因此，LRH-1代表了代谢的新型治疗靶点疾病。 LRH-1与磷脂（PLS）结合，并被不寻常的PL dilauroylphosphophatidyl胆碱激活（DLPC）显示有效的抗糖尿病作用。 LRH-1受PL配体调节的发现揭示了调整LRH-1活性以治疗代谢疾病的令人兴奋的潜力。但是，PL不稳定并且不适合临床使用，因此需要发展小分子激动剂。这证明了这一点到目前为止，具有挑战性，由于很少的小分子可以从大型亲脂性中取代内源性脂质装订口袋。我们实验室的最新研究表征了一类能够实现的小分子壮举。使用强大的SAR和创新的化学，我们设计了有效的LRH-1激动剂生物活性。我们已经修改了我们最有效和有效的激动剂，以改善其生物物理特性，使其适合体内研究。作为治疗剂的LRH-1激动剂的进步由于缺乏适当的啮齿动物模型来筛选潜在候选者，因此也受到阻碍啮齿动物和人LRH-1的结合袋中的序列差异。为了克服这个障碍，我们使用了 CRISPR-CAS9策略使小鼠LRH-1配体结合口袋人性化。这允许通过合成激动剂同时最大程度地减少内源相互作用表面的变化。这些以领先复合开发和小鼠模型产生，结合我们对LRH-1的深入了解结构和功能，创建一个理想的平台，以开发候选临床前LRH-1调节器代谢疾病。在这里，我们制定了一种策略来定义行动机制，目标参与，我们的铅化合物的药理学和疾病功效。在AIM 1中，我们生成改进的化合物模仿PL样激活的生物物理特性。我们将执行这些机械表征化合物探索如何与不同的极性部分接触PL结合位点可以改善LRH-1 激活。在AIM 2中，我们将从公认的角度研究铅化合物的行为。这主要目标是使用我们的人源化小鼠建立化合物的易干性，以便可以建立药代动力学关系。在AIM 3中，我们将使用我们的人源化小鼠和一个模型饮食引起的肥胖症评估我们铅LRH-1化合物的体内功效以改善葡萄糖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.

DOI：
10.1042/bst20210419
发表时间：
2021-11-01
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
通讯作者：

Hydroarylation of Arenes via Reductive Radical-Polar Crossover.

DOI：
10.1021/jacs.0c03926
发表时间：
2020-05-20
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Flynn AR;McDaniel KA;Hughes ME;Vogt DB;Jui NT
通讯作者：
Jui NT

Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.

DOI：
10.1016/j.bmcl.2020.127293
发表时间：
2020-08-15
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Cornelison JL;Cato ML;Johnson AM;D'Agostino EH;Melchers D;Patel AB;Mays SG;Houtman R;Ortlund EA;Jui NT
通讯作者：
Jui NT