The Design and Study of Anticancer Therapeutics Inspired by Natural Substrates of LAT1

受 LAT1 天然底物启发的抗癌治疗药物的设计和研究

基本信息

批准号：
10580214
负责人：
Karelle Aiken
金额：
$ 42.47万
依托单位：
GEORGIA SOUTHERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-08 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580214
关键词：
Acridines Address Affinity Amino Acid Transport System L Amino Acid Transporter Amino Acids Anthraquinones Antineoplastic Agents Azoles Biochemical Biological Biological Assay Biological Factors Cancer Cell Growth Cancer cell line Cancerous Carboxylic Acids Cause of Death Cell Death Cell Proliferation Cell Survival Cells Cellular Morphology Confocal Microscopy Coumarins Data Dependence Disease Disease Progression Dose Drug Design Drug Monitoring Drug Targeting Evaluation Fluorescence Goals Histidine Hydrophobicity Immunochemistry In Vitro Intake Investigation Isoleucine Leucine Link Malignant Neoplasms Metabolic Methionine Morphology Naphthoquinones Neoplasm Metastasis Neutral Amino Acid Transport Systems Nuclear Nutrient Outcome Pathway interactions Penetration Pharmaceutical Preparations Pharmacotherapy Phenylalanine Production Property Publishing Reactive Oxygen Species Recurrence Recurrent disease Reporting Resistance Side Signal Pathway Signal Transduction Structure Structure-Activity Relationship TP53 gene Therapeutic Time Triazoles Tryptophan Tumor Suppressor Genes Tyrosine Valine Vertebral column Work analog anti-cancer anti-cancer therapeutic anticancer activity cancer cell cancer type chemotherapeutic agent cytotoxic design drug candidate drug development drug resistance development gene function innovation meetings neoplastic cell novel novel therapeutics overexpression quinoline response scaffold screening skeletal small molecule success targeted delivery therapy resistant tumor tumor progression unnatural amino acids uptake virtual

项目摘要

PROJECT SUMMARY Cancer’s uncontrolled cell proliferation is supported in part by the overexpression of the large neutral amino acid transporter 1 (LAT1). LAT1 is key in meeting the unusually high nutrient demand of cancer cells for natural- occurring hydrophobic amino acids. The proposed work is significant because current drug treatments suffer from limitations involving the poor selectivity for cancer cells over healthy cells, inefficient drug-uptake, and treatment-resistance which often occurs with progression and recurrence of the disease. Furthermore, a major roadblock in drug development for cancerous tumors is the inability of many small molecules to penetrate into tumor cells. An effective strategy for addressing these drawbacks involves targeting drugs that are amenable for uptake via LAT1. The expected outcome in designing structures that can serve as LAT1 substrates is targeted delivery through enhanced drug selectivity for cancer cells over healthy cells. The overarching goal of this project is to develop novel 1,2,3-triazole-based amino acid chemotherapeutics as structural analogues of natural LAT1 substrates. 1,2,3-Triazoles are important scaffolds in compounds with a wide range of biological activities, including anticancer activity. In addition, these units are often attached to other biologically active molecules to enhance potency. Anticancer drug designs that take advantage of the therapeutic potential of the 1,2,3-triazole rings in combination with the uptake efficiency that can be achieved via LAT1 are innovative, novel, and wide open for exploration. The approach to this project will be carried out with two specific aims, (1) the design and synthesis of the triazole-based amino acid-drug assemblies and (2) in vitro characterization of drug candidates. In the first aim, we will design three classes of amino acid analogues containing the 1,2,3-triazolyl rings linked to aromatic (Ar) moieties with known anticancer activity. The core skeletal designs will consist of an unnatural amino acid backbone, the natural amino acid tyrosine, and meta-tyrosine; the latter two are highly compatible with LAT1. Biological evaluation of the final triazole amino acid-drug assemblies and their precursors will be used to decipher the structure-activity relationship for anticancer activity and cellular uptake. The second aim will focus on the biological studies. These investigations will use cell viability studies to probe the anticancer properties of the compounds developed in aim 1. The second aim will also probe intracellular delivery; morphological changes in the cells post drug administration; and signaling pathways and biochemical parameters the molecules are predicted to target (p53 tumor suppressor gene function and reactive oxygen species (ROS) production).

项目概要癌症不受控制的细胞增殖在一定程度上是由大中性氨基酸的过度表达支持的转运蛋白 1 (LAT1) 是满足癌细胞异常高的天然营养需求的关键。疏水性氨基酸的研究意义重大，因为目前的药物治疗受到影响。其局限性包括对癌细胞相对于健康细胞的选择性差、药物摄取效率低以及此外，随着疾病的进展和复发，通常会出现治疗抵抗。癌症肿瘤药物开发的障碍是许多小分子无法渗透到解决这些缺点的有效策略是针对适合肿瘤细胞的药物。通过 LAT1 摄取的预期结果是设计可用作 LAT1 底物的结构的预期结果。通过增强对癌细胞相对于健康细胞的药物选择性来进行递送是该项目的总体目标。旨在开发新型 1,2,3-三唑基氨基酸化疗药物作为天然 LAT1 的结构类似物 1,2,3-三唑是具有广泛生物活性的化合物的重要支架。此外，这些单元通常与其他生物活性分子连接以发挥抗癌活性。增强利用 1,2,3-三唑治疗潜力的抗癌药物设计。环与可通过 LAT1 实现的吸收效率相结合，具有创新性、新颖性和广泛性该项目的方法将有两个具体目标：（1）设计和基于三唑的氨基酸-药物组装体的合成和（2）药物的体外表征在第一个目标中，我们将设计三类含有 1,2,3-三唑基的氨基酸类似物。与具有已知抗癌活性的芳香族（Ar）部分连接的环，核心骨架设计将由一个非天然氨基酸主链，天然氨基酸酪氨酸和间位酪氨酸含量很高；与最终三唑氨基酸-药物组装体及其前体的生物学评价兼容。第二个将用于破译抗癌活性和细胞摄取的结构-活性关系。目标将集中在生物学研究上，这些研究将利用细胞活力研究来探索抗癌作用。目标 1 中开发的化合物的特性。第二个目标还将探讨细胞内递送；给药后细胞的形态变化；以及信号通路和生物化学分子预计靶向的参数（p53 肿瘤抑制基因功能和活性氧物种（ROS）生产）。