SCIENTIFIC ADVANCES

From the Sea to Clinical Trials

Dr. William Fenical at the Scripps Institution of Oceanography (SIO), University of California at San Diego (UCSD), is an internationally recognized leader in the field of marine natural products. His research has received sustained NCI support and he currently holds a MERIT award for his pioneering work in marine microbe-based drug discovery.

Despite historical successes with antitumor antibiotics, over the past several decades the efficacy of antibiotics and anticancer drugs derived from microbial sources has diminished due in large part to development of drug resistance. Traditional terrestrial microbial sources for new drugs leads are yielding reduced returns after years of intensive research. Exploring the world’s vast unexplored oceans for marine microbes as a source for new microbes and novel drug leads was thought to be a rewarding endeavor. Dr. Fenical and his team combined marine microbiology techniques with modern drug discovery tools, explored deep ocean sediments, and made the seminal discovery of a new genus of obligate marine actinomycetes, named salinospora, from deep ocean sediments.

Dr. Fenical’s work has continued to focus on genetically unique marine microbes, and he and his team have found new strains of obligate marine microbes that require seawater to grow in culture. Through morphology and 16S rRNA phylogenic analyses, these new bacteria represent the first major actinomycete taxon reported exclusively from the sea. This finding is significant as it provides further evidence of the important roles actinomycetes play in marine ecology and biocomplexity. He and his team have found a number of novel biologically active compounds, two of which are currently in phase I development. One is salinosporamide A, which has an unusual fused r-lactam-b-lactone bicyclic structure and is a potent 20S proteasome inhibitor (IC₅₀ 1.3 nM). The compound has been licensed to Nereus Pharmaceuticals and is in phase I clinical development for the treatment of multiple myeloma, lymphomas, and solid tumors. Due to the success of bortezomib, which has received marketing approval for the treatment of multiple myeloma, the proteasome is a high interest drug target. In preclinical studies, this drug appears superior to bortezomib and shows: 1) a broader and longer lasting proteasome inhibition profile; 2) efficacy against bortezomib-, lenalidomide-, thalidomide-, and dexamethasone-resistant tumor cells from multiple myeloma patients; 3) efficacy against a wider range of tumors, including many solid tumor models; 4) less cytotoxicity to normal cells; 5) a 7- to 10-fold higher in vivopotency; 6) potential for administration both orally and by intravenous injection on a once-a-week schedule; 7) marked enhancement of efficacy when used in combination with chemotherapeutics and biologics such as bevacizumab, cetuximab, irinotecan, FOLFOX, FOLFIRI, and oxaliplatin. Recently, Dr. Bradley Moore, also of SIO at UCSD, and collaborators have completed the genome sequence of the producing strain, and his team discovered and subsequently characterized a novel chlorination pathway by which salinosporamide incorporates the chlorine atom, which is key to the drug’s ability to bind to the proteasome. Genetic engineering of the pathway can lead to analogs not available in nature. These exciting developments clearly demonstrate the potential of finding new chemical entities as cancer drugs from natural sources.

Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W. Salinosporamide A: A highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Eng2003:42;355–7.
http://www.ncbi.nlm.nih.gov/pubmed/12548698

Groll M, Huber R, Potts BC. Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J Am Chem Soc2006:128;5136–41.
http://www.ncbi.nlm.nih.gov/pubmed/16608349

Fenical W, Jensen PR. Developing a new resource for drug discovery: marine actinomycete bacteria. Nat Chem Biol2006:2;666–73.
http://www.ncbi.nlm.nih.gov/pubmed/17108984

Eustáquio AS, Pojer F, Noel JP, Moore BS. Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nat Chem Biol2008:4;69–74.
http://www.ncbi.nlm.nih.gov/pubmed/18059261