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