Discovery and Mechanistic Characterization of New Cytotoxic Agents from Marine Cyanobacteria

摘要 癌症是世界范围内的一个主要健康问题，也是美国第二大死因。 尽管癌症研究取得了重大进展，但现有的治疗方法仍面临以下限制 耐药性、特异性和毒性，迫切需要发现新的抗癌药物。几项研究 例证了海洋蓝藻在提供化学上多样化的有效细胞毒剂方面的作用，这些毒剂通过 新的机制。高效利用海洋蓝藻繁殖的结构空间 计划中的战略将对癌症研究领域产生重大影响。因此，我们筛选蓝藻 新的/新的细胞毒素的样本，并用全面的机制研究来补充我们的发现 指定与治疗相关的生物靶点。具体地说，从形态上和从 系统发育上的新蓝藻被优先用于提取。提取物会影响癌细胞的活力。 分析指导的分级，结合LC MS和核磁共振去复制策略。结构将是 用核磁共振法和质谱法测定。具有耐人寻味的结构新颖性和强效的化合物 选择性活动受到机械论的描述。对细胞目标的公正评估是 对开采新的生物/靶标是必要的。因此，我们实施了通用的方法，可以准确地 扰乱的生物途径和潜在的分子靶标。同时，在以下情况下采用有针对性的方法 已鉴定的细胞毒素的结构特征表明，潜在的药效团与已知的相互作用 蛋白质。我们利用化学基因组学方法成功地确定了抗真菌细胞毒素苦杏仁内酯A的靶点 剖析和有针对性的方法。此外，通过使用等基因筛选系统，我们内置了 在发现过程中进行选择性筛选，以确定已识别的新细胞毒素是否为 致癌的KRAS和HIF途径，因为与正常细胞相比，这些途径在癌症中被激活。 这项拟议的工作将确定新的/新的细胞毒剂，这将导致新的抗癌疗法。 此外，它们作为化学探针的评估将拓宽我们许多生物过程的广度。最后， 这项研究有可能揭示新的生物靶点空间，这对癌症具有巨大的价值。 研究。

Abstract Cancer is a major health problem worldwide and is the second leading cause of death in the United States. Despite the significant advances in cancer research, available therapies still encounter limitations such as resistance, specificity and toxicity, which urgent the discovery of new anticancer agents. Several studies exemplified marine cyanobacteria's role in providing chemically diverse potent cytotoxic agents that act via novel mechanisms. Harnessing the structural space reproduced by marine cyanobacteria in an efficient planned strategy would significantly impact the cancer research field. Therefore, we screen cyanobacterial samples for new/novel cytotoxins and complement our discovery with comprehensive mechanistic studies to assign the therapeutically relevant biological targets. Specifically, samples derived from morphologically and phylogenetically novel cyanobacteria are prioritized for extraction. Extracts are subjected to cancer cell viability assay guided fractionation, coupled with LCMS and NMR dereplication strategies. Structures will be determined using NMR and mass spectrometry. Compounds with intriguing structural novelty and potent or selective activity are subjected to mechanistic characterization. An unbiased assessment of cellular targets is necessary to mine for novel biology/targets. Therefore, we implement universal approaches that could pinpoint perturbed biological pathways and potential molecular targets. In parallel, targeted approaches are employed if structural features of the identified cytotoxin suggest potential pharmacophores with known interacting proteins. We successfully identified targets of the antifungal cytotoxin amantelide A using chemogenomic profiling and targeted approaches. In addition, through the use of an isogenic screening system, we built in selectivity screening in the discovery process to determine if identified new cytotoxins are inhibitors of the oncogenic KRAS and HIF pathways, since these pathways are activated in cancer compared with normal cells. The proposed work will identify new/novel cytotoxic agents that would serve leads to new anticancer therapies. Besides, their assessment as chemical probes would widen our breadth of many biological processes. Finally, this study has the potential to inform new biological target space, which is of tremendous value to cancer research.