Molecularly targeted natural products discovery from diverse natural sources

从不同的天然来源发现分子靶向天然产物

• 批准号: 8763546
• 负责人: Kirk Gustafson
• 金额: $ 92.1万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763546
• 关键词: Adenosine Triphosphate; Advanced Malignant Neoplasm; Alkaloids; Architecture; Binding; Biological; Biological Assay; Biological Factors; Biological Process; Biology; CCR; Cancer cell line; Chemicals; Chemistry; Collection; Coupling; Cyanobacterium; Development; Developmental Therapeutics Program; Disseminated Malignant Neoplasm; Drug Transport; Evaluation; Exhibits; Fractionation; Genes; Goals; HIV; Information Technology; Laboratories; Lead; Malignant Neoplasms; Marine Invertebrates; Marines; Mediating; Molecular; Molecular Conformation; Molecular Target; Natural Products Chemistry; Nucleic Acids; Oncogenic; Pathway interactions; Plant Sources; Plant alkaloid; Plants; Play; Process; Proteins; Research; Resources; Role; Source; Structure; Therapeutic Agents; Transcription Factor AP-1; Transcriptional Activation; Translating; Translations; Tumor Promotion; United States National Institutes of Health; Work; assay development; bHLH-PAS factor HLF; base; biological systems; cell motility; cellular targeting; chemosensitizing agent; cytotoxic; cytotoxicity; in vivo; inhibitor/antagonist; insight; interest; novel; pre-clinical; repository; screening; tool; transcription factor; tumor progression

Our research efforts combine molecular target-based discovery with natural products chemistry. Natural products are a source of structural complexity and biological activity that can provide insight on the function of new targets, pathways, or modes of action. They play an important role in dissecting and understanding the intricacies of cancer development, progression, and treatment so continued discovery efforts are highly appropriate for new potential anticancer applications. We work to discover and define the chemistry of compounds that are active in a particular biological system, meaning those that effectively modulate the molecular target of interest, regardless of whether they are new or previously known chemical entities. Thus, appropriate strategies for the selection, prioritization, bioassay-guided fractionation, and dereplication of active extracts were developed to facilitate efficient lead identification. Working in conjunction with our colleagues and collaborators, we successfully undertook studies to identify inhibitors of Activator Protein-1 (AP-1) an oncogenic transcription factor associated with tumor promotion and progression. Our goal was to find compounds that inhibited AP-1 over a broad concentration range before they resulted in cytotoxicity. A total of 29 active compounds were isolated and identified from these extracts with 24 from plant sources, 2 from a marine invertebrate, 2 from a cyanobacterium, and 1 from a fungal extract. The most promising AP-1 inhibitor we obtained was a plant alkaloid known as cephaeline. It is a low micromolar inhibitor of AP-1 that specifically blocked transcriptional activation of AP-1 dependent genes and reduced cellular migration and invasion by a metastatic cancer cell line. A natural product screening effort to discover inhibitors of the multidrug resistance transporter known as Adenosine triphosphate-Binding Cassette protein G2 (ABCG2) provided the marine alkaloid botryllamide G as the lead development compound. Botryllamide G exhibited robust inhibition of ABCG2-mediated drug transport and low cytotoxic activity. It appears to function as a true inhibitor of ABCG2 and not a competitive substrate, that binds to and alters the conformation of the transporter that disrupts its efflux function. A synthesis of botryllamide was developed and it is now undergoing in vivo preclinical development studies. A screening campaign for inhibitors of the oncogenic transcription factor Hypoxia Inducible Factor 2 alpha (HIF-2alpha) identified 31 active extracts that were subjected to bioassay-guided fractionation studies. Fifty five purified compounds were obtained and 33 were provided to our CCR collaborators for ongoing secondary biological evaluation. Natural products that can inhibit the cellular entry or replication of the human immunodeficiency virus (HIV) are also of interest. Novel HIV inhibitory cyclicpeptides have been isolated and identified from a variety of terrestrial plant and marine sources.

我们的研究工作将联合收割机基于分子靶点的发现与天然产物化学相结合。天然产物是结构复杂性和生物活性的来源，可以提供对新靶点，途径或作用模式功能的见解。它们在解剖和理解癌症发展、进展和治疗的复杂性方面发挥着重要作用，因此持续的发现工作非常适合新的潜在抗癌应用。我们致力于发现和定义在特定生物系统中具有活性的化合物的化学性质，这意味着那些有效调节目标分子的化合物，无论它们是新的还是以前已知的化学实体。因此，开发了用于活性提取物的选择、优先化、生物测定引导的分级分离和去复制的适当策略，以促进有效的铅鉴定。与我们的同事和合作者一起工作，我们成功地进行了研究，以确定激活蛋白-1（AP-1）的抑制剂，AP-1是一种与肿瘤促进和进展相关的致癌转录因子。我们的目标是找到在导致细胞毒性之前在宽浓度范围内抑制AP-1的化合物。从这些提取物中共分离鉴定出29种活性化合物，其中24种来自植物，2种来自海洋无脊椎动物，2种来自蓝藻，1种来自真菌提取物。我们获得的最有希望的AP-1抑制剂是一种植物生物碱，称为头孢菌素。它是AP-1的低微摩尔抑制剂，特异性阻断AP-1依赖性基因的转录激活，并减少转移性癌细胞系的细胞迁移和侵袭。一项旨在发现多药耐药转运蛋白（称为三磷酸腺苷结合盒蛋白G2（ABCG 2））抑制剂的天然产物筛选工作提供了海洋生物碱botryllamide G作为主要开发化合物。Botryllamide G表现出对ABCG 2介导的药物转运的稳健抑制和低细胞毒性活性。它似乎作为ABCG 2的真正抑制剂而不是竞争性底物发挥作用，结合并改变转运蛋白的构象，破坏其外排功能。开发了葡萄糖酰胺的合成方法，目前正在进行体内临床前开发研究。致癌转录因子缺氧诱导因子2 α（HIF-2 α）抑制剂的筛选活动确定了31种活性提取物，这些提取物进行了生物测定指导的分级分离研究。获得了55种纯化的化合物，并将33种提供给我们的CCR合作者进行持续的二级生物学评价。可以抑制人类免疫缺陷病毒（HIV）进入细胞或复制的天然产物也是令人感兴趣的。新的HIV抑制性环肽已从多种陆生植物和海洋来源中分离和鉴定。