This is a competitive renewal application to continue to explore marine microorganisms as a new source for antitumor-antibiotics. The proposed project would continue as a collaboration between chemists and microbiologists at the Scripps Institution of Oceanography in La Jolla, CA. and cancer biologists at the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, NJ. Studies proposed for the renewal period include the following: - The isolation, cultivation and biological evaluation of marine microorganisms from diverse habitats. The focus of the renewal application will be on 7 new groups of obligate marine actinomycetes (Salinospora, Marinomyces, and the MAR 3-7 groups) discovered during the past 24 months. - Overall, to continue to isolate and describe new molecules which show novel mechanisms of action in cancer-relevant, mechanism-based screens, show in vitro tissue type selectivity in the NCI 60 cell line and BMS ODCA panels, and to subsequently investigate their in vivo efficacies. - To focus a screening effort on the new cancer relevant targets IGF-1 Growth Factor, DMA Methyl Transferase-1 (DNMT-1), CoactivatorAssociated Arginine Methyltransferase (CARM-1) and Ceramidase, and on yeast selective DMA repair and cell checkpoint targets. These goals will also be supplemented at SIO with several assays which focus on infectious diseases (screening against drug resistant pathogens and for inhibitors of two selected bacterial efflux pumps). - To continue to advance previous discoveries (Salinosporamide A, Halimide, Sargassamide A and several other molecules) for in vivo evaluation in the BMS P388 and L1210 leukemias and the murine solid tumor models M109, Mam16/C and M50766.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37CA044848-26S1
Application #
8544520
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fu, Yali
Project Start
1987-04-15
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
26
Fiscal Year
2012
Total Cost
$77,500
Indirect Cost
$27,500
Name
University of California San Diego
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Jensen, Paul R; Moore, Bradley S; Fenical, William (2015) The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery. Nat Prod Rep 32:738-51
Choi, Eun Ju; Nam, Sang-Jip; Paul, Lauren et al. (2015) Previously Uncultured Marine Bacteria Linked to Novel Alkaloid Production. Chem Biol 22:1270-9
Leutou, Alain S; Yang, Inho; Kang, Heonjoong et al. (2015) Nocarimidazoles A and B from a Marine-Derived Actinomycete of the Genus Nocardiopsis. J Nat Prod 78:2846-9
Nam, Sang-Jip; Kauffman, Christopher A; Jensen, Paul R et al. (2015) Actinobenzoquinoline and Actinophenanthrolines A-C, Unprecedented Alkaloids from a Marine Actinobacterium. Org Lett 17:3240-3
Álvarez-Micó, Xavier; Rocha, Danilo D; Guimarães, Larissa A et al. (2015) The Hybrid Pyrroloisoindolone-Dehydropyrrolizine Alkaloid (-)-Chlorizidine A Targets Proteins within the Glycolytic Pathway. Chembiochem 16:2002-6
Trzoss, Lynnie; Fukuda, Takashi; Costa-Lotufo, Letícia V et al. (2014) Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin. Proc Natl Acad Sci U S A 111:14687-92
Jensen, Paul R; Chavarria, Krystle L; Fenical, William et al. (2014) Challenges and triumphs to genomics-based natural product discovery. J Ind Microbiol Biotechnol 41:203-9
Farnaes, Lauge; La Clair, James J; Fenical, William (2014) Napyradiomycins CNQ525.510B and A80915C target the Hsp90 paralogue Grp94. Org Biomol Chem 12:418-23
Farnaes, Lauge; Coufal, Nicole G; Kauffman, Christopher A et al. (2014) Napyradiomycin derivatives, produced by a marine-derived actinomycete, illustrate cytotoxicity by induction of apoptosis. J Nat Prod 77:15-21
Alvarez-Mico, Xavier; Jensen, Paul R; Fenical, William et al. (2013) Chlorizidine, a cytotoxic 5H-pyrrolo[2,1-a]isoindol-5-one-containing alkaloid from a marine Streptomyces sp. Org Lett 15:988-91

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