Development of Small Molecule Mimetics of hepatocyte Growth Factor (HGF)

描述（由申请人提供）：天然存在的细胞因子肝细胞生长因子（HGF），也称为散点因子（SF），活跃于全身的许多组织中，参与血管生成、器官发生、组织修复和神经诱导的调节。HGF在许多正常细胞类型中具有丝裂性，包括肝细胞、血管内皮细胞和黑色素细胞；2)促进上皮细胞分支管状结构形成的形态原；3)通过其抗凋亡活性发挥细胞保护作用，并通过对抗TGFbeta1-Smad信号传导发挥抗纤维化作用。HGF的所有生物学效应都是通过刺激其细胞表面受体c-Met而触发的，并伴随下游效应通路的激活。最近发表的几项研究证明了外源性给药SF/HGF在肾、肺和肝纤维化动物模型中的治疗潜力。将HGF注入损伤的肝组织表明，这种细胞因子在促进组织修复和器官再生以及减少纤维化方面是有效的。肝硬化是一种终末期肝病，常由丙型肝炎感染或长期酗酒引起，HGF可有效减轻肝硬化的结构性损害。鉴于它的治疗潜力，人们对能够激活c-Met的HGF模拟物的开发越来越感兴趣。迄今为止，hgf衍生的肽和c-Met激活抗体已经开发出来，但这些基于多肽的模拟物不稳定且昂贵。为了克服这些缺点，我们将开发HGF活性的小分子模拟物。在Aim 1中，我们将使用我们的LRD（有限理性设计）方法设计这样的小分子，并使用合成有机技术合成它们。在目标2中，我们将在上皮细胞培养模型中测试我们新开发的化合物的活性。

DESCRIPTION (provided by applicant): The naturally-occurring cytokine hepatocyte growth factor (HGF), also known as scatter factor(SF), is active in numerous tissues throughout the body, participating in the regulation of angiogenesis, organogenesis, tissue repair and neural induction. HGF is 1) mitogenic in many normal cell types, including hepatocytes, vascular endothelial cells, and melanocytes; 2) a morphogen that promotes the formation of branched tube-like structures in epithelial cells; 3) cytoprotective by virtue of its anti-apoptotic activity and exerts anti-fibrotic effects by opposing TGFbeta1-Smad signaling. All biological effects of HGF are triggered by stimulating its cell surface receptor c-Met, with concomitant activation of downstream effector pathways. Several recently published studies have documented the therapeutic potential of exogenously administered SF/HGF in animal models of renal, pulmonary and liver fibrosis. Administration of HGF into injured liver tissue suggests that the cytokine is effective in promoting tissue repair and organ regeneration and in reducing fibrosis. HGF effectively alleviates the structural damage seen in liver cirrhosis, an end-stage liver disease that is frequently caused by Hepatitis C infection or long-term alcohol abuse. Given it's therapeutic potential, there is heightened interest in the development of HGF mimetics that can activate c-Met. To date, an HGF-derived peptide and c-Met activating antibodies have been developed, yet those polypeptide-based mimetics are unstable and expensive. To overcome these shortcomings, we will develop small molecule mimetics of HGF activity. In Aim 1, we will design such small molecules using our LRD (Limited rational design) approach and synthesize them using synthetic organic technology. In aim 2, we will test the activity of our newly developed compounds in epithelial cell culture models.