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: 8553211
• 负责人: Kirk Gustafson
• 金额: $ 139.89万
• 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/8553211
• 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; Screening procedure; 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; 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.

我们的研究工作将基于分子目标的发现与天然产品化学结合在一起。天然产品是结构复杂性和生物活性的来源，可以提供有关新目标，途径或作用方式的功能的见解。他们在剖析和理解癌症发展，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活跃的化合物的化学，这意味着那些有效调节感兴趣的分子靶标的化合物，无论它们是新的还是以前已知的化学实体。因此，制定了适当的选择，优先级，生物测定指导的分级和进行活性提取物的策略，以促进有效的铅识别。与我们的同事和合作者一起工作，我们成功进行了研究，以鉴定激活蛋白-1（AP-1）的抑制剂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产生细胞毒性之前抑制AP-1的化合物。从这些提取物中分离出29种活性化合物，并从植物来源中鉴定出29种活性化合物，并从植物源中鉴定出2个来自海洋无脊椎动物的24个提取物，其中2个来自蓝细菌的2个，来自蓝细菌，1个来自燃料提取物。我们获得的最有前途的AP-1抑制剂是一种称为头孢赛的植物生物碱。 它是AP-1的低微摩尔抑制剂，该抑制剂特异性阻断了AP-1依赖性基因的转录激活，并降低了转移性癌细胞系的细胞迁移和侵袭。 自然产品筛查的工作，以发现被称为三磷酸腺苷结合盒蛋白G2（ABCG2）的多药耐药转运蛋白抑制剂（ABCG2）提供海洋生物碱 - 葡萄晶G的铅作为铅发育化合物。 Botryllamide G表现出强烈的ABCG2介导的药物转运和低细胞毒性活性的抑制作用。它似乎是ABCG2的真正抑制剂，而不是竞争性底物，它与破坏其外排功能的转运蛋白结合并改变了转运蛋白的构象。开发了杂化合酰胺的合成，现在正在进行体内临床前开发研究。筛查致癌转录因子缺氧缺氧诱导因子2α（HIF-2Alpha）的抑制剂，确定了31种活性提取物，这些活性提取物被生物测定引导的分数研究。获得了55种纯化的化合物，并向我们的CCR合作者提供了33种以进行次级生物学评估。自然产物可以抑制人类免疫缺陷病毒（HIV）的细胞进入或复制。新型的HIV抑制性循环肽已被分离并从各种陆地植物和海洋来源鉴定出来。