Novel Targeted Anticancer Agents from Marine Cyanobacteria

PROJECT SUMMARY Cyanobacteria are among the most ancient organisms on Earth and have evolved chemical weapons for defensive purposes, which we are exploiting for anticancer drug discovery. Our past research has exemplified that marine cyanobacteria produce compounds with exceptionally potent activity and/or possess novel mechanisms of action or act on new binding sites, including various tubulin-targeting agents. Dolastatin 10 had the greatest clinical impact so far, leading to several FDA-approved antibody-drug conjugates (ADCs). The clinical success of these ADCs with a dolastatin 10-based cytotoxic payload as well as success of other natural products drugs acting on different pharmacological sites of tubulin suggest that targeting different sites may lead to different pharmacological consequences and new drug classes. Our discovery of gatorbulin is a new prime example for such natural product because it acts on a novel tubulin binding site. We will build on previous discoveries and gradually shift towards rational optimization and preclinical studies, while maintaining a strong pipeline based on new sourcing strategies, coupled with an augmented innovative screening platform predictive of clinical activity. We apply a multidimensional screening platform focused on overcoming drug resistance in solid tumors and hematologic malignancies, using innovative primary and secondary assays. We also integrate a synthetic chemistry component into our cancer research program in order to perform rigorous biological studies, to help solve the supply problem, and to improve on the activities of our natural products prioritized for further developmental studies. Specifically, we will carry out field collections of marine cyanobacteria, targeting underexplored species, and also explore a unique culture collection. We will prepare libraries, perform dereplication, subject the samples to a set of phenotypic primary assays and designed secondary assays to prioritize the potentially most impactful samples. Prioritized samples will be subjected to bioassay-guided isolation of the active compounds. Structures will be determined using NMR and mass spectrometry. Several scaffolds have already been prioritized based on novelty, targets and activity. We will design improved analogues and assess their activity and selectivity profiles. One new pharmacologically-active compound class will be advanced to in vitro and in vivo preclinical pharmacology.