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

• 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
• 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

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).

项目总结 癌症不受控制的细胞增殖在一定程度上是由大的中性氨基酸的过度表达支持的 传送器1(LAT1)。LAT1是满足癌细胞对天然营养物质异常高的营养需求的关键。 出现疏水性氨基酸。这项拟议的工作意义重大，因为目前的药物治疗 从癌细胞对健康细胞较差的选择性、药物摄取效率低下以及 随着疾病的进展和复发而经常出现的治疗耐药。此外，一位少校 癌症药物开发的障碍是许多小分子无法穿透 肿瘤细胞。解决这些缺点的一个有效策略是将目标对准那些可用于 通过LAT1吸收。设计可用作LAT1衬底的结构的预期结果是有针对性的 通过增强癌细胞对健康细胞的药物选择性来传递药物。这个项目的首要目标是 是开发基于1，2，3-三氮唑的新型氨基酸化疗药物作为天然LAT1的结构类似物 底物。1，2，3-三唑类化合物是一类具有广泛生物活性的重要骨架化合物， 包括抗癌活性。此外，这些单元通常连接到其他生物活性分子上以 增强战斗力。利用1，2，3-三氮唑治疗潜力的抗癌药物设计 环与可通过LAT1实现的摄取效率相结合，是创新、新颖和广泛的 开放进行探索。这一项目的实施将有两个具体目标：(1)设计和 三唑类氨基酸药物组装体的合成及(2)药物的体外表征 候选人。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 与芳香族(Ar)部分相连的环，具有已知的抗癌活性。核心骨架设计将由一个 非天然氨基酸骨架，天然氨基酸酪氨酸和偏酪氨酸；后两者高度 与LAT1兼容。三氮唑氨基酸药物组装体及其前体的生物评价 将用于破译抗癌活性和细胞摄取的结构-活性关系。第二 AIM将专注于生物学研究。这些研究将使用细胞活性研究来探索抗癌 目标1中开发的化合物的性质。第二个目标还将探索细胞内给药； 给药后细胞的形态变化；信号通路和生化 预测分子靶向的参数(P53、肿瘤抑制基因功能和活性氧 物种(ROS)生产)。