The primary goal of this research program is to discover new natural products that will lead to novel anti-cancer drugs. Overall, we expect to generate a large number of exciting new natural products for development as novel anti-cancer agents using the powerful tools of microbial genomics, combinatorial biology, combinatorial biosynthesis, natural products chemistry and innovative anti-cancer drug screening assay systems. This will be accomplished by using two powerful molecular genetic approaches for creation of complex natural products along with sophisticated """"""""smart assays"""""""" for molecular-based screening at Novartis Pharmaceuticals. Five research groups will work together to access unique marine microbial genomes, generate combinatorial biology and combinatorial biosynthesis libraries, culture and extract novel metabolites, screen extracts for anti-cancer biological activity and characterize new chemical entities. Project #1 is headed by Dr. Amy Wright at Harbor Branch Oceanographic Institution (HBOI) who will collect and characterize novel marine actinomycetes. Dr. Peter McCarthy at HBOI will direct the core facility and manage microbial genomic DNA preparation, fermentation and extraction for the combinatorial biology clones. Project #2 is headed by Dr. David H. Sherman at the University of Minnesota, the overall P.I., who will direct the combinatorial biology as well as combinatorial biosynthesis efforts for the entire program. The administrative core will also be managed by Dr. Sherman. Team #3 is headed by Dr. Kenneth Blair of the Oncology Department at Novartis Pharmaceuticals. His group will be responsible for high throughput screening using """"""""smart assays"""""""" developed for anti-cancer drug discovery. Project #4, headed by Dr. William Gerwick at Oregon State University, will focus on isolation and characterization of novel marine cyanobacteria for generation of combinatorial biology libraries. His group will also participate in combinatorial biosynthesis work on the curacin A polyketide synthase. Project #5 of this highly collaborative and interactive effort, headed by Dr. Phillip Crews of U.C. Santa Cruz, will focus on isolation and identification of novel marine microbes, including sponge- derived actinomycetes, myxobacteria and fungi. His laboratory will provide genomic source material for combinatorial biology as well as for combinatorial biosynthesis on the latrunculin A polyketide synthase. Both the Wright, Gerwick and Crews laboratories will each provide natural products purification and structure elucidation support. In summary, unique compound structural diversity will be generated by this multi- disciplinary collaboration.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA083155-06
Application #
6798569
Study Section
Special Emphasis Panel (ZCA1-SRRB-7 (M2))
Program Officer
Fu, Yali
Project Start
1999-09-23
Project End
2005-08-31
Budget Start
2003-09-10
Budget End
2005-08-31
Support Year
6
Fiscal Year
2003
Total Cost
$884,259
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ramaswamy, Aishwarya V; Sorrels, Carla M; Gerwick, William H (2007) Cloning and biochemical characterization of the hectochlorin biosynthetic gene cluster from the marine cyanobacterium Lyngbya majuscula. J Nat Prod 70:1977-86
Beck, Zachary Q; Sherman, David H (2006) Development of an internally quenched fluorogenic substrate for kinetic analysis of thioesterases. Anal Biochem 349:309-11
Magarvey, Nathan A; Beck, Zachary Q; Golakoti, Trimurtulu et al. (2006) Biosynthetic characterization and chemoenzymatic assembly of the cryptophycins. Potent anticancer agents from cyanobionts. ACS Chem Biol 1:766-79
Beck, Zachary Q; Aldrich, Courtney C; Magarvey, Nathan A et al. (2005) Chemoenzymatic synthesis of cryptophycin/arenastatin natural products. Biochemistry 44:13457-66
Fortman, J L; Sherman, David H (2005) Utilizing the power of microbial genetics to bridge the gap between the promise and the application of marine natural products. Chembiochem 6:960-78
Chang, Zunxue; Sitachitta, Namthip; Rossi, James V et al. (2004) Biosynthetic pathway and gene cluster analysis of curacin A, an antitubulin natural product from the tropical marine cyanobacterium Lyngbya majuscula. J Nat Prod 67:1356-67
Wright, Amy E; Chen, Ying; Winder, Priscilla L et al. (2004) Lasonolides C-g, five new lasonolide compounds from the sponge Forcepia sp. J Nat Prod 67:1351-5
Edwards, Daniel J; Marquez, Brian L; Nogle, Lisa M et al. (2004) Structure and biosynthesis of the jamaicamides, new mixed polyketide-peptide neurotoxins from the marine cyanobacterium Lyngbya majuscula. Chem Biol 11:817-33
Salomon, Christine E; Magarvey, Nathan A; Sherman, David H (2004) Merging the potential of microbial genetics with biological and chemical diversity: an even brighter future for marine natural product drug discovery. Nat Prod Rep 21:105-21
Magarvey, Nathan A; Keller, Jessica M; Bernan, Valerie et al. (2004) Isolation and characterization of novel marine-derived actinomycete taxa rich in bioactive metabolites. Appl Environ Microbiol 70:7520-9

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