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

描述(申请人提供)：自然产生的细胞因子肝细胞生长因子(HGF)，也被称为散射因子(SF)，活跃于全身众多组织中，参与血管生成、器官形成、组织修复和神经诱导的调节。HGF是1)许多正常细胞类型，包括肝细胞、血管内皮细胞和黑素细胞中的有丝分裂原；2)促进上皮细胞中分支管样结构形成的形态原；3)由于其抗凋亡活性而具有细胞保护作用，并通过对抗TGFbeta1-Smad信号而发挥抗纤维化作用。HGF的所有生物学效应都是通过刺激其细胞表面受体c-Met来触发的，同时伴随着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予SF/HGF在肾、肺和肝纤维化动物模型中的治疗潜力。在受损的肝组织中应用HGF表明，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。HGF有效地减轻了肝硬变的结构损害，肝硬变是一种终末期肝病，通常由丙型肝炎感染或长期酗酒引起。鉴于其治疗潜力，人们对能够激活c-Met的HGF模拟物的开发兴趣高涨。到目前为止，已经开发出一种HGF衍生肽和c-Met激活抗体，但这些基于多肽的模拟物不稳定且价格昂贵。为了克服这些缺点，我们将开发HGF活性的小分子模拟分子。在目标1中，我们将使用我们的LRD(有限理性设计)方法设计这种小分子，并使用合成有机技术来合成它们。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。 公共卫生相关性：在动物模型中，肝细胞生长因子(HGF)是一种自然产生的细胞因子，已被证明有助于在肝炎感染期间和肝移植期间的肝损伤恢复。它也是治疗慢性肝病(肝硬变)的唯一有效方法，这种疾病会导致肝脏结疤和功能稳步下降。肝硬变最常见的原因是丙型肝炎感染和长期酗酒。然而，HGF的生产成本很高，而且制造的蛋白质不稳定，不适合用于治疗。为了避免这些问题，我们将开发HGF的小分子模拟物，与重组HGF相比，它具有同等或更好的疗效和特异性，而且生产成本更低，更容易管理。

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. PUBLIC HEALTH RELEVANCE: Administration of Hepatocyte Growth Factor (HGF), a naturally occurring cytokine, has proven beneficial for the recovery from liver injury during hepatitis infection and during liver transplantation in animal models. It is also the only efficient treatment for chronic liver disease (cirrhosis) that causes a scarring of the liver and steady decline of its function. Cirrhosis is most often caused by Hepatitis C infection and long-term alcohol abuse. However, HGF production is expensive and the manufactured protein is not stable, making it unsuitable for therapeutic use. To circumvent these problems, we will develop small molecule mimetics of HGF that work with equal or better efficacy and specificity and are cheaper to produce and easier to administer than recombinantly made HGF.