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:
- 金额:$ 42.47万
- 依托单位:
- 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:
- 关键词:AcridinesAddressAffinityAmino Acid Transport System LAmino Acid TransporterAmino AcidsAnthraquinonesAntineoplastic AgentsAzolesBiochemicalBiologicalBiological AssayBiological FactorsCancer Cell GrowthCancer cell lineCancerousCarboxylic AcidsCause of DeathCell DeathCell ProliferationCell SurvivalCellsCellular MorphologyConfocal MicroscopyCoumarinsDataDependenceDiseaseDisease ProgressionDoseDrug DesignDrug MonitoringDrug TargetingEvaluationFluorescenceGoalsHistidineHydrophobicityImmunochemistryIn VitroIntakeInvestigationIsoleucineLeucineLinkMalignant NeoplasmsMetabolicMethionineMorphologyNaphthoquinonesNeoplasm MetastasisNeutral Amino Acid Transport SystemsNuclearNutrientOutcomePathway interactionsPenetrationPharmaceutical PreparationsPharmacotherapyPhenylalanineProductionPropertyPublishingReactive Oxygen SpeciesRecurrenceRecurrent diseaseReportingResistanceSideSignal PathwaySignal TransductionStructureStructure-Activity RelationshipTP53 geneTherapeuticTimeTriazolesTryptophanTumor Suppressor GenesTyrosineValineVertebral columnWorkanaloganti-canceranti-cancer therapeuticanticancer activitycancer cellcancer typechemotherapeutic agentcytotoxicdesigndrug candidatedrug developmentdrug resistance developmentgene functioninnovationmeetingsneoplastic cellnovelnovel therapeuticsoverexpressionquinolineresponsescaffoldscreeningskeletalsmall moleculesuccesstargeted deliverytherapy resistanttumortumor progressionunnatural amino acidsuptakevirtual
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).
项目摘要
癌症不受控制的细胞增殖部分是由大的中性氨基酸的过度表达支持的
转运蛋白1(LAT 1)。LAT 1是满足癌细胞对天然营养素异常高的需求的关键。
存在疏水性氨基酸。这项拟议中的工作意义重大,因为目前的药物治疗受到
从局限性,涉及癌细胞对健康细胞的选择性差,药物摄取效率低,
治疗抵抗,其通常随着疾病的进展和复发而发生。此外,主要
癌症肿瘤药物开发的障碍是许多小分子不能渗透到肿瘤细胞中,
肿瘤细胞解决这些缺点的有效策略涉及靶向药物,
通过LAT 1摄取。设计可用作LAT 1底物的结构的预期结果是有针对性的
通过增强的药物选择性递送癌细胞超过健康细胞。这个项目的首要目标是
是开发新的基于1,2,3-三唑的氨基酸化学治疗剂作为天然LAT 1的结构类似物
印刷受体. 1,2,3-三唑类化合物是一类重要的骨架化合物,具有广泛的生物活性,
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,
增强效力。利用1,2,3-三唑治疗潜力的抗癌药物设计
环与可通过LAT 1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
候选人第一个目标是设计三类含1,2,3-三唑基的氨基酸类似物
与具有已知抗癌活性的芳族(Ar)部分连接的环。核心骨架设计将包括一个
非天然氨基酸骨架、天然氨基酸酪氨酸和间酪氨酸;后两者是高度非天然氨基酸骨架。
与LAT 1兼容。最终三唑氨基酸-药物组装体及其前体的生物学评价
将被用于破译抗癌活性和细胞摄取的结构-活性关系。第二
aim将侧重于生物学研究。这些研究将使用细胞活力研究来探测抗癌药物。
目的1中开发的化合物的性质。第二个目标也将探测细胞内递送;
给药后细胞的形态学变化;以及信号传导途径和生物化学
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)产生)。
项目成果
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