新型维甲酸受体（RAR）激动剂的筛选及其功能调控机理研究

项目名称： 新型维甲酸受体（RAR）激动剂的筛选及其功能调控机理研究

项目编号： No.31200571

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 杨春燕

作者单位： 厦门大学

项目金额： 20万元

中文摘要： 维甲酸受体（retinoic acid receptor，RAR）的配体具有减缓或阻抑细胞增殖的作用，已广泛应用于多种癌症的治疗中。然而目前大多数已发现的RAR配体都在结构上与维甲酸（retinoic acid，RA）相似，具有强烈的副作用和广泛的细胞耐药性，这些都限制了维甲酸类RAR配体的临床应用。通过对化合物库的高通量筛选，我们发现了一种全新的RAR配体Luffariellolide，其结构不同于维甲酸，具有抗癌活性，且能够克服维甲酸的耐药性。本项目拟通过一系列结构生物学、分子生物学、生物化学和细胞生物学方法进一步探讨该配体的生理功能，得到RARs-配体复合物的晶体结构，从原子水平阐明该配体对RARs转录调控机理，并进一步揭示该配体在RAR介导疾病中的信号通路机制。从而提出一种基于该配体的设计策略以研发用于抑制肿瘤生长，且减轻副作用和耐药性的有效药物。

中文关键词： 维甲酸受体；Luffariellolide；结构；抗癌；共价结合

英文摘要： Retinoic acid receptor (RAR) ligands slow or arrest the growth of many transformed cell lines and have been used as therapeutic agents for various cancers. However, many RAR ligands so far are structurally related to retinoids, which have been associated with many undesired side effects and also drug resistance that limit further development and clinical application of retinoid-based therapeutic agents. We identified a novel RAR ligand, Luffariellolide, with a chemical structure distinct from RA by high-throughput compound library screening. Functional characterization revealed that luffariellolide displays chemotherapeutic potentials for overcoming RA resistance, suggesting that luffariellolide may have advantages over current RA drugs. Our study intends to further asses the roles of Luffariellolide in the physiological function of RARs and study the RARs-Luffariellolide complex structure by using a multidisciplinary approach including structural biology, molecular and cell biology, and biochemistry. Therefore, the biochemical mechanism of RAR activation by Luffariellolide will be elucidated, and the role of Luffariellolide in the signal path of RAR related diseases will be unravelted, which may provide an new antitumor drug design strategy for non-RA compounds with less drug resistance and adverse effects.

英文关键词： RAR；Luffariellolide；structure；antitumor；covalent-binding