Small-molecule analysis of signaling pathways

信号通路的小分子分析

• 批准号: 6970435
• 负责人: MOTONARI UESUGI
• 金额: $ 26.66万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-20 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970435
• 关键词: antineoplastics; binding proteins; biological signal transduction; inhibitor /antagonist; insulinlike growth factor; intermolecular interaction; pharmacokinetics; protein binding; protein purification; protein quantitation /detection; small interfering RNA; small molecule; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Insulin-like growth factors (IGFs) are strong mitogens for a variety of cancer cells, and their overexpression increases the likelihood of tumor development and the tendency to metastasize. The involvement of IGFs in a range of human malignancies suggests that the molecular analysis of IGF regulation leads to a better understanding of human cancers and possibly a new cancer therapy or prevention. The P.l.'s laboratory has been discovering and analyzing molecular pathways that modulate the functions of IGF2, an IGF that is over expressed in human hepatocellular carcinoma, by using the small molecule called 94G6. The drug-like molecule was originally isolated from a chemical library in the P.l.'s laboratory as an inhibitor of insulin-induced adipogenesis, and subsequent assays showed that 94G6 selectively inhibits the viability and growth of IGF2-overexpressing hepatocellular carcinoma cells at the IC50 of 30 nM. Preliminary experiments in the P.l.'s laboratory suggest that one of the targets of 94G6 is MFP-2, a poorly studied protein with unknown function. The binding of 94G6 to MFP-2 appears to activate transcription factor STAT6 and blocks IGF2 functions by expressing proteins including cellular IGF inhibitor IGFBP-1 and cytokine/insulin suppressor SOCS-3. In this application, we plan to further our analysis of the 94G6 pathway and its related ones by a combination of cell biological, molecular biological, biochemical, and organic chemical experiments. The 94G6 pathway may play a role in the regulation of IGF signals and insulin resistance in human cells, and might reveal a crosstalk among cancer, diabetes, and inflammation. Small organic molecules, whether natural or synthetic, have been utilized for discovering and analyzing disease-linked signaling pathways. 94G6 may become another good example of such small molecules.

描述（由申请人提供）：胰岛素样生长因子（IGF）是多种癌细胞的强丝分裂原子，其过表达增加了肿瘤发育的可能性和转移的趋势。 IGF在一系列人类恶性肿瘤中的参与表明，IGF调节的分子分析可以更好地了解人类癌症，并可能是一种新的癌症治疗或预防。 P.L.的实验室一直在发现和分析调节IGF2功能的分子途径，IGF2是一种使用称为94G6的小分子，在人肝细胞癌中过度表达的IGF。 该药物样分子最初是从P.L.实验室中的化学文库中分离出来的，作为胰岛素诱导的脂肪形成的抑制剂，随后的测定表明，94G6选择性地抑制IC50 nm IC50的IC50的IGF2过表达的IGF2过表达的肝细胞癌细胞的生存能力和生长。 P.L.实验室中的初步实验表明，94G6的目标之一是MFP-2，这是一种研究不明的蛋白质，功能不明。 94G6与MFP-2的结合似乎通过表达包括细胞IGF抑制剂IGFBP-1和细胞因子/胰岛素抑制socs-3的蛋白质来激活转录因子Stat6并阻断IGF2功能。在此应用中，我们计划通过结合细胞生物学，分子生物学，生化和有机化学化学实验来进一步分析94G6途径及其相关途径。 94G6途径可能在人类细胞中IGF信号和胰岛素抵抗的调节中起作用，并且可能揭示癌症，糖尿病和炎症之间的串扰。小的有机分子（无论是天然还是合成）已用于发现和分析疾病连接的信号通路。 94G6可能成为如此小的分子的另一个很好的例子。