Targeting the orphan nuclear receptor LRH-1 with small molecules

肥胖在美国日益流行，导致非酒精性脂肪性肝病（NAFLD）、心血管疾病和2型糖尿病的病例增加。这些疾病的一个共同特征是脂质和糖代谢异常。这一建议的中心是核激素受体，肝脏受体同源物1 (LRH-1)，它是脂质代谢、逆向胆固醇转运、葡萄糖感知和体内平衡的重要调节因子。因此，LRH-1代表了代谢性疾病的一个新的治疗靶点。LRH-1与磷脂（PLs）结合，但直到最近，PLs在受体激活中的作用尚不清楚。最近的研究发现，二氯酰磷脂酰胆碱（DLPC）是一种特异性的LRH-1激动剂，具有有效的抗糖尿病作用。尽管这种尚未开发的治疗潜力，LRH-1受配体调节的机制仍然知之甚少。LRH-1受PL配体调节的发现揭示了调节LRH-1活性以治疗代谢性疾病的令人兴奋的潜力。然而，PLs（如DLPC）不稳定，不适合临床使用，因此需要开发小分子激动剂。到目前为止，这已经被证明是具有挑战性的，因为很少有小分子能够从大的亲脂结合口袋中取代内源性脂质。我们实验室最近的初步研究表明，一类有效的小分子具有这种能力。我们的LRH-1结合这些激动剂的晶体结构揭示了受体激活的新机制，并为提高激动剂活性的策略提供了见解。本提案的总体目标是利用基于结构的合理设计方法开发改进的小分子调节剂。x射线晶体学结合氢氘交换质谱，细胞分析和动物研究将用于解决这一目标的一系列三个目标。目的1。设计和合成强效、有效和选择性的LRH-1调节剂确定RJW100类似物对LRH-1变构调节的分子基础评价LRH-1调节剂作为肥胖患者的抗糖尿病药物的疗效。

Obesity is a growing epidemic in the United States, leading to increases in cases of nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and type 2 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), but until recently, the role of PLs in receptor activation was unclear. Recent studies identified dilauroylphosphatidylcholine (DLPC) as a specific LRH-1 agonist with potent anti-diabetic effects. Despite this untapped therapeutic potential, mechanisms through which LRH-1 is regulated by ligands remain poorly understood. 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 (such as DLPC) 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 are capable of displacing endogenous lipids from the large, lipophilic binding pocket. Recent preliminary studies in our lab have characterized a potent class of small molecules that are capable of this feat. Our crystal structures of LRH-1 bound to a set of these agonists have uncovered novel mechanisms of receptor activation and have provided insights into strategies to improve agonist activity. The overall goal of this proposal is to develop improved small molecule modulators using a structure-based, rational design approach. X-ray crystallography combined with hydrogen deuterium exchange mass spectrometry, cellular assays, and animal studies will be used to address this goal in a series of three Aims. Aim 1. Design and synthesize potent, effective, and selective LRH-1 modulators Aim 2. Determine the molecular basis of allosteric modulation of LRH-1 by RJW100 analogues Aim 3. Evaluate the efficacy of LRH-1 modulators as anti-diabetic agents in obesity.