Anticancer drug discovery from marine Cyanobacteria

Charles Benjamin Naman

Appointment Period: 2015-2017, Grant Year: [29, 30]

Our lab has an established research program investigating the secondary metabolites of marine cyanobacteria for anticancer drug discovery. Crude extracts of these materials are subjected to in vitro whole-cell cytotoxicity testing against H460 human lung cancer cells in our lab, as well as against other cancer cell types through existing collaborations. Active samples are subjected to advanced chemical analyses, such as LC-MS/MS molecular networking and HSQC-based NMR dereplication against state of the art commerical and proprietary databases to determine the degree of novelty of their chemical constituents. Through bioassay-guided iosolation research, single chemical components are then purified from active extracts. These pure molecules are determined structurally using extensive spectroscopic, spectrometric or X-ray crystallographic techniques. Purified checmical entities are tested in vitro, as before, to determine their cytotoxic activites. Pure componunds that have been prioritized by their in vitro potency, structural features, and available quantities are being studied through an existing collaboration with Fred Valeriote, for their pharmacokinetic properties and in vivo anticancer efficacy. In serveral cases, we have utilized synthetic organic chemistry to produce more of a given anticancer natural product, as well as analog stuctures, to develop an understanding of the critical features of the new drug molecular for its biological properties.

In conjuction with the Protemics Core Facility at Wayne State University, the mechanisms of action of the most promising new anticancer agents are also being investigated. This reserach is being conducted through quantitative proteomics and quantitative phosphoproteomics after in vitro whole-cell testging. Additionally, complementary information about the mechanism of action is obtained by using a yeast strain that does not efficiently export toxic test compounds and can thus rapidly develop resistance, and was developed by collaborators in the Winzeler laboratory at UCSD. Yeast strains that develop resistance to our anticancer drug leads are subjected to genome sequencing, and the results are compared to the wild type to allow for the determination of the genes that have mutated. This research is thus strongly focused on the discovery of new anticancer drugs from marine cyanobacteria, and to promote their development through investigations of their mechanisms of action and structure activity relationships.

PUBLICATIONS (resulting from this training)

Trainee recently appointed to grant: publications are still in progress.