Targeting the orphan nuclear receptor LRH-1 with small molecules

肥胖在美国是一种日益增长的流行病，导致非酒精性脂肪肝（NAFLD），心血管疾病和2型糖尿病病例的增加。这些疾病的共同特征是异常的脂质和葡萄糖代谢。该建议集中在核激素受体，肝受体同源物1（LRH-1），其作为脂质代谢，胆固醇逆向转运，葡萄糖传感和稳态的重要调节剂。因此，LRH-1代表了代谢疾病的新治疗靶点。LRH-1与磷脂（PL）结合，但直到最近，PL在受体活化中的作用尚不清楚。最近的研究确定二月桂酰磷脂酰胆碱（DLPC）作为一种特异性的LRH-1激动剂，具有强效的抗糖尿病作用。尽管这种未开发的治疗潜力，LRH-1通过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，PL（如DLPC）是不稳定的并且不适合于临床使用，需要开发小分子激动剂。迄今为止，这已被证明具有挑战性，因为很少有小分子能够从大的亲脂性结合口袋中置换内源性脂质。我们实验室最近的初步研究已经确定了一类能够实现这一壮举的有效小分子。我们的LRH-1结合到一组这些激动剂的晶体结构已经发现了受体激活的新机制，并提供了对改善激动剂活性的策略的见解。该提案的总体目标是使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法、细胞测定和动物研究将用于在一系列三个目标中实现这一目标。目标1。设计和合成强效、有效和选择性的LRH-1调节剂确定RJW 100类似物对LRH-1变构调节的分子基础。评估LRH-1调节剂作为抗糖尿病药物治疗肥胖症的疗效。

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.