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

项目摘要 真核细胞启动因子(EIFs)在多种人类疾病中的过度表达已有报道 包括乳腺癌(BC)。我们的目标是开发基于松烷天然产物的工具化合物 有选择地瞄准EIF。大约15%-20%的乳腺癌病例的特征是三阴性乳房 癌症(TNBC)，一种缺乏有效靶向治疗方式的亚型，1并经常受到 因此，有必要发现新的化学物质，它可以选择性地 有针对性的TNBC，以降低与这种疾病相关的死亡率。 我们已经证明，abietane天然产物衍生物(SJ38)显著减少蛋白质的合成。 并在TNBC细胞模型中靶向eIF2/eIF4信号轴。我们发现a)SJ38选择性地抑制 癌细胞在低微摩尔范围内的活性(&lt；10μM)，而不影响非癌乳腺上皮 细胞活力或信号，b)SJ38显著降低涉及蛋白质的调节因子的表达 细胞培养中氨基酸稳定同位素标记(SILAC)蛋白质组学提供的基因 SJ38主要针对蛋白质合成的本体分析和独创性途径分析表明 SJ38主要通过eIF2、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，重点是翻译控制。我们的 研究解决了在发现新的治疗剂和潜在治疗的生物靶点方面的知识差距 TNBC。我们假设SJ38可以减缓乳腺癌的进展，并通过 翻译控制。我们提出了以下具体目标：1)开发一种新的综合策略来访问 一系列不同的abietane衍生物，以促进结构活性关系(SAR)和目标参与 学习。2)确定所生成的化合物作为蛋白质合成调节剂的生物学特性，以及 它们在TNBC细胞模型中抑制增殖和迁移的能力。3)确定通过哪些机制 松柏烷以癌细胞模型为靶标。 影响：拟议研究的结果将为制定有针对性的目标提供关键知识 成功治疗包括癌症在内的人类疾病所需的治疗战略。

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.