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).

项目摘要 癌症的不受控制的细胞增殖得到了部分支持大型中性氨基酸的过表达 转运蛋白1（LAT1）。 LAT1是满足癌细胞对天然的异常营养需求的关键 - 发生疏水氨基酸。拟议的工作很重要，因为目前的药物治疗遭受了 来自涉及癌细胞对健康细胞的选择性差的局限性，效率低下的药物摄取和 耐药性的耐药性通常是随着疾病的进展和复发而发生的。此外，专业 在药物开发中进行取消肿瘤的障碍是许多小分子无法渗透到 肿瘤细胞。解决这些缺点的有效策略涉及针对适合的药物 通过LAT1吸收。设计可以用作LAT1基材的结构中的预期结果是针对的 通过增强对癌细胞的药物选择性超过健康细胞的药物选择性。该项目的总体目标 是开发新型的1,2,3-三唑基化学治疗剂作为天然LAT1的结构类似物 基材。 1,2,3-三唑是具有广泛生物学活性的化合物中的重要脚手架， 包括抗癌活性。另外，这些单元通常连接到其他具有生物活性的分子上 提高效力。利用1,2,3-三唑的治疗潜力的抗癌药物设计 戒指与可以通过LAT1实现的吸收效率相结合是创新的，新颖的和广泛的 开放探索。该项目的方法将以两个具体的目的进行，（1）设计和 基于三唑的氨基酸 - 药物组件的合成和（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 与具有已知抗癌活性的芳香族（AR）部分相关的环。核心骨骼设计将包括 非天然氨基酸主链，天然氨基酸酪氨酸和元酪氨酸；后两个很高 与LAT1兼容。最终三唑氨基酸 - 药物组件及其前体的生物学评估 将用于破译抗癌活性和细胞摄取的结构活性关系。第二个 AIM将集中于生物学研究。这些研究将使用细胞活力研究来探测抗癌 AIM 1中开发的化合物的性能。第二个目标还将探测细胞内递送； 细胞药物给药细胞的形态变化；以及信号通路和生化 参数预测分子被预测为靶标（p53肿瘤抑制基因功能和活性氧 物种（ROS）生产）。