University of Florida College of Pharmacy researchers have identified the marine cyanobacterial genus Dapis as the natural source of dolastatin 15, an anticancer compound from one of the most impactful families of marine natural products.
The research provides the first genomic characterization of Dapis, revealing the genes and biological processes responsible for dolastatin 15 production. The findings establish a framework for connecting valuable natural products to their biological origins, an important step in developing new cancer therapies.
The study was published in the Proceedings of the National Academy of Sciences of the United States of America, or PNAS, and was supported by the National Institutes of Health.
“We know from our decades of research that cyanobacteria produce many different anticancer agents and other bioactive compounds, but no one really has an understanding of how many of them are made,” said Hendrik Luesch, Ph.D., a professor of medicinal chemistry and the Debbie and Sylvia DeSantis Chair in Natural Products Drug Discovery and Development in the UF College of Pharmacy. “Once we understand their origins, we can envision ways to produce and further optimize these compounds through synthetic biology or biotechnological approaches.”
Marine organisms are a rich source of structurally diverse natural products, with more than 35,000 compounds identified to date. These natural products have inspired important medicines, including cancer treatments. But for many of the compounds, scientists have been unable to identify the organisms that produce them or the genes responsible for their biosynthesis.
“It’s tremendously difficult to isolate these products,” said Yousong Ding, Ph.D., a professor of medicinal chemistry in the UF College of Pharmacy and the study’s senior author. “Nature typically produces them in very small amounts, and it can be difficult to determine which organism is actually responsible for producing them. In nature, you also rarely find a single strain in isolation. Instead, these organisms exist as communities, which makes it challenging to pinpoint the source of a particular compound.”
UF researchers addressed that challenge with dolastatin 15, a member of the dolastatin family of natural products. Dolastatins are among the most clinically impactful families of compounds associated with marine cyanobacteria, commonly known as blue-green algae.
First discovered in the 1980s, dolastatins have had a lasting influence on cancer drug development. Dolastatin 10, the family’s best-known member, has served as the foundation for six FDA-approved drugs since 2011. There are more than 100 clinical trials underway involving dolastatin 10-based drug candidates.
Dolastatin 15 is the second major compound in the family and has shown potential as a cancer treatment. Analogues of dolastatin 15 have also entered clinical trials. Until now, researchers had not definitively identified its biological source or fully understood the genes responsible for producing it.
The new study identifies Dapis, a previously underexplored genus of marine cyanobacteria, as the producer of dolastatin 15. The compound used in the research was isolated from samples collected in Guam.
“What is interesting about this finding is that nature is using two different species of cyanobacteria to produce two very similar natural products,” Ding said. “Both compounds have very potent anticancer activity and target the same protein involved in cancer, yet they are produced by different organisms.”
For Luesch, who also serves as the director of the UF Center for Natural Products, Drug Discovery and Development, a member of UF Health Cancer Institute and a professor of the Program in Cancer and Stem Cell Biology at Duke-NUS Medical School, the discovery builds upon more than two decades of research.
As a graduate student in 2001, Luesch published the first scientific paper linking dolastatin 10 to marine cyanobacteria collected from the Pacific Ocean. Since then, his research team has collected and analyzed cyanobacteria from around the world to identify biologically active natural products and better understand how they are made.
The identification of Dapis marks another significant milestone.
“It has come full circle,” Luesch said. “Decades ago, we hypothesized that these compounds were not produced by the sea hare, but rather cyanobacteria. In 2024, we closed the loop for dolastatin 10. When we first isolated and reported dolastatin 15 in 2020, we had circumstantial evidence, but we could not directly link it to the organism that produced it or to the genes responsible. Now we have pinpointed the source, and it turned out to be a previously underexplored genus of cyanobacteria that is an untapped resource for drug discovery. Through bioinformatics and machine learning, we also obtained insights into the evolution of the gene cluster, which may guide medicinal chemistry efforts.”
The PNAS publication was co-authored by Luesch and Ding, as well as Manyun Chen, Ph.D., M.S., and Ranjala Ratnayake, Ph.D., from the UF College of Pharmacy’s Department of Medicinal Chemistry, and Steven Bruner, Ph.D., a professor of chemistry at UF, along with members of their research teams. Other co-authors included Valerie Paul, Ph.D., from the Smithsonian Marine Station and Mohamed Donia, Ph.D., and his research group from Princeton University.