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

阐明松香烷类药物的作用方式以开发潜在的治疗药物_补充剂

基本信息

批准号：
10798580
负责人：
Fatima R Rivas
金额：
$ 5.51万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要在各种人类疾病中，已经报道了真核引发因子（EIF）的过度表达包括乳腺癌（BC）。有选择地靶向EIF。癌症（TNBC）是一种缺乏有效的靶向治疗方式的亚型，1，经常受到困扰。 2因此，有必要发现可以选择性地的新化学物质靶向TNBC降低与该疾病相关的死亡率。我们已经表明，Abietane天然产物衍生物（SJ38）显着降低蛋白质合成和靶EIF2/EIF4信号轴TNBC细胞模型中。低微摩尔范围（<10μm）的癌细胞生存能力，同时不感兴趣的非癌性乳腺上皮细胞活力或信号传导，b）SJ38 SJ38显着降低了与蛋白质有关的规律性因素的表达合成和c）在细胞培养（SILAC）蛋白质组学中使用氨基酸的稳定同位素标记已证明基因 SJ38主要针对蛋白质合成和Ingenuity途径分析的本体分析表明， SJ38主要通过EIF2和EIF4/P70S6K信号通路发挥其抗癌作用。我们的长期目标是阐明TNBC的SJ38分子机制，重点是转化研究解决了知识的差距，以发现新的治疗剂和生物学靶标的潜在治疗 TNBC。我们假设SJ38降低了乳腺癌的进展，并通过翻译控制。我们提出以下特定目的：1）一系列不同的Abietane衍生物，以促进结构活动关系（SAR）和目标参与研究。它们在TNBC地窖模型中抑制增殖和迁移的能力。 Abietanes靶向癌细胞模型。影响：支撑研究的结果将提供批判性知识向往朝向目标的发展治疗策略已为成功治疗包括癌症在内的人类疾病而进行。