Cyanobacterial pseudo-natural products for anticancer drug discovery

用于抗癌药物发现的蓝藻伪天然产物

• 批准号: 10663360
• 负责人: Eduardo Javier Caro
• 金额: $ 15万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10663360
• 关键词: Address; Antibody-drug conjugates; Antineoplastic Agents; Architecture; Biological; Biological Assay; Biological Process; Cancer cell line; Cells; Characteristics; Chemicals; Chemistry; Coupled; Coupling; Cyanobacterium; Data; Development; Drug Design; Evaluation; Evolution; Exclusion; FDA approved; Goals; Growth; Hodgkin Disease; Hybrids; In Vitro; Knowledge; Lead; Libraries; Machine Learning; Malignant Neoplasms; Mass Spectrum Analysis; Modernization; Molecular; Natural Products; Nuclear Magnetic Resonance; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Plants; Principal Component Analysis; Process; Property; Protons; Publishing; Reaction; Reporting; Research; Role; Screening for cancer; Source; Structure; Synthesis Chemistry; Techniques; Technology; Therapeutic; Therapeutic Agents; Tissues; anti-cancer; anticancer activity; artificial intelligence method; cancer cell; chemical synthesis; combinatorial chemistry; computational intelligence; computerized tools; cytotoxicity; density; design; drug development; drug discovery; drug-like compound; fungus; liquid chromatography mass spectrometry; metabolomics; natural product inspired; novel therapeutics; pharmacophore; predictive tools; quantum; scaffold; screening; secondary metabolite; small molecule; small molecule libraries; social; software development; success

PROJECT ABSTRACT Cyanobacteria produce secondary metabolites have been well-documented to possess potent and selective anticancer activity, which has resulted in FDA approval of a cyanobacterial antibody-drug-conjugate (ADC) for the treatment of several Hodgkin lymphomas. Even though this highlights the critical role of natural products in the drug discovery, the novelty of structural scaffolds has largely remained steady in the last two decades. Therefore, we aim to design and synthesize a pseudo-natural product library inspired by cyanobacterial metabolites with well-described anti-cancer activity to expand their molecular coverage. Our pseudo-natural product library will develop and describe uncharted chemical space that integrates privileged scaffolds while employing medicinal chemistry approaches, such as combinatorial chemistry and parallel synthesis. We will qualitatively and quantitatively characterize our library using modern computational, machine learning and metabolomic techniques, to compare it with natural products and FDA-approved drugs. The long-term goal of this research is to generate a chemical library rich in natural product scaffolds that are biased towards cancer tissue for drug discovery and development. Our main hypothesis is that our library will contain chemical architectures embedded with biological properties of privileged cyanobacterial structures that describe new chemical space.

项目摘要 蓝细菌产生的次生代谢产物已有充分记录 有效和选择性抗癌活性，这导致了FDA的批准 蓝细菌抗体 - 毒与缀合物（ADC）用于治疗几种霍奇金 淋巴瘤。即使这突出了天然产品在药物中的关键作用 发现，结构脚手架的新颖性在过去两个中基本保持稳定 几十年。因此，我们旨在设计和综合伪自然产品库 受蓝细菌代谢物具有良好描述的抗癌活性的启发 它们的分子覆盖范围。我们的伪自然产品库将开发和描述 在使用药用时，未知的化学空间会整合特权脚手架 化学方法，例如组合化学和平行合成。我们将 定性和定量地使用现代计算的图书馆来表征我们的库， 机器学习和代谢组技术，将其与天然产品和 FDA批准的药物。这项研究的长期目标是生成化学库 丰富的天然产物脚手架偏向于癌组织进行药物发现 和发展。我们的主要假设是我们的图书馆将包含化学 嵌入特权蓝细菌结构的生物学特性的体系结构 描述了新的化学空间。