Discovery and Mechanistic Characterization of New Cytotoxic Agents from Marine Cyanobacteria

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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.