Elucidating the mode of action of the abietanes to develop potential therapeutic agents

阐明松香烷的作用模式以开发潜在的治疗药物

• 批准号: 10580286
• 负责人: Fatima R Rivas
• 金额: $ 41.18万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580286
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Address; Amino Acids; Award; Biological; Biological Assay; Biological Models; Biology; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Epithelial Cells; Cancer Biology; Cancer Model; Cell Culture Techniques; Cell Death; Cell Survival; Cell model; Cells; Cessation of life; Chemicals; Cyclization; Data; Development; Disease; Endoplasmic Reticulum; Environment; Estrogen receptor positive; Eukaryotic Initiation Factors; Gel; Gene Expression Regulation; Genes; Genetic Translation; Goals; Knowledge; Label; Lead; Libraries; Louisiana; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Methodology; Modality; Modeling; Molecular; Natural Products; Neoplasm Metastasis; Normal Cell; Ontology; Pathway Analysis; Pathway interactions; Pharmaceutical Chemistry; Pharmacology; Phenotype; Prognosis; Property; Protein Biosynthesis; Proteome; Proteomics; Reagent; Regulatory Pathway; Reporting; Research; Rhodium; Series; Signal Pathway; Signal Transduction; Site; Stable Isotope Labeling; Structure-Activity Relationship; Students; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Traditional Medicine; Translations; United States; Universities; anti-cancer; base; breast cancer progression; cancer cell; cancer recurrence; cancer subtypes; clinically relevant; cytotoxic; drug discovery; efficacy testing; human disease; improved; inhibitor; innovation; malignant breast neoplasm; migration; model development; mortality; new therapeutic target; novel; novel therapeutics; overexpression; polysome profiling; programs; scaffold; stem; targeted treatment; tool; transcriptome; triple-negative invasive breast carcinoma

PROJECT ABSTRACT Over expression of eukaryotic initiation factors (eIFs) has been reported in various human diseases including breast cancer (BC). Our objective is to develop tool compounds based on the abietane natural products to selectively target eIFs. Approximately 15-20% breast cancer cases are characterized as triple negative breast cancer (TNBC), a subtype that lacks effective targeted therapy modalities,1 and is often plagued with dysfunctional eIFs expression.2 Therefore, there is a need to discover new chemical matter that could selectively targeted TNBC to reduce mortality rates associated with this disease. We have shown that abietane natural product derivatives (SJ38) significantly reduce protein synthesis and target eIF2/eIF4 signaling axis in TNBC cellular models. We discovered that a) SJ38 selectively inhibits cancer cell viability at the low micromolar range (<10μM) while not affecting non-cancerous mammary epithelial cell viability or signaling, b) SJ38 significantly reduces the expression of regulatory factors involved in protein synthesis, and c) Stable isotope labeling with amino acids in cell culture (SILAC) proteomics provided Gene Ontology analysis that SJ38 mainly targeted protein synthesis and Ingenuity Pathway Analysis suggested that SJ38 exerts its anticancer effects primarily through the eIF2, and eIF4/p70S6K signaling pathway. Our long-term goal is to elucidate SJ38 molecular mechanism in TNBC focusing on translational control. Our study addresses a gap in knowledge to discover new therapeutic agents and biological targets to potentially treat TNBC. We hypothesize that SJ38 reduces breast cancer progression and sensitizes cells to therapy via translational control. We propose the following specific aims: 1) Develop a novel synthetic strategy to access a series of diverse abietane derivatives to facilitate structure activity relationship (SAR), and target engagement studies. 2) Determine the biological properties of the generated compounds as protein synthesis modulators and their capability to inhibit proliferation and migration in TNBC cellular models. 3) Identify the mechanism by which the abietanes target cancer cellular models. IMPACT: Results from the proposed studies will provide critical knowledge towards the development of targeted therapeutic strategies needed for the successful treatment of human diseases including cancer.

项目摘要 据报道，真核起始因子（eIF）在多种人类疾病中过度表达 包括乳腺癌（BC）。我们的目标是开发基于松香天然产物的工具化合物 选择性地针对 eIF。大约 15-20% 的乳腺癌病例属于三阴性乳腺癌 癌症（TNBC）是一种缺乏有效靶向治疗方式的亚型，1并且经常受到以下问题的困扰 eIF 表达功能失调。2 因此，需要发现新的化学物质，可以选择性地 针对 TNBC 以降低与该疾病相关的死亡率。 我们已经证明松香烷天然产物衍生物 (SJ38) 显着减少蛋白质合成 并针对 TNBC 细胞模型中的 eIF2/eIF4 信号轴。我们发现 a) SJ38 选择性抑制 低微摩尔范围 (<10μM) 下的癌细胞活力，同时不影响非癌性乳腺上皮 细胞活力或信号转导，b) SJ38 显着降低参与蛋白质的调节因子的表达 c) 细胞培养物中氨基酸的稳定同位素标记 (SILAC) 蛋白质组学提供的基因 本体分析表明SJ38主要针对蛋白质合成，Ingenuity Pathway Analysis表明： SJ38主要通过eIF2和eIF4/p70S6K信号通路发挥抗癌作用。 我们的长期目标是阐明 SJ38 在 TNBC 中的分子机制，重点关注翻译控制。我们的 研究填补了知识空白，以发现新的治疗药物和潜在治疗的生物靶点 TNBC。我们假设 SJ38 通过以下途径减少乳腺癌进展并使细胞对治疗敏感 平移控制。我们提出以下具体目标：1）开发一种新颖的合成策略来获取 一系列不同的松香烷衍生物，以促进结构活性关系 (SAR) 和目标参与 研究。 2) 确定生成的化合物作为蛋白质合成调节剂的生物学特性和 它们在 TNBC 细胞模型中抑制增殖和迁移的能力。 3) 确定机制 松香内酯针对癌症细胞模型。 影响：拟议研究的结果将为制定有针对性的药物提供关键知识。 成功治疗包括癌症在内的人类疾病所需的治疗策略。