Metastin – does your oncologist test for this?

Metastin – does your oncologist test for this?

Bioorganic & Medicinal Chemistry Letters
Volume 16, Issue 1, 1 January 2006, Pages 134-137

   
   

 

Abstract

Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity

 

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Ayumu Niidaa, Zixuan Wangb, Kenji Tomitaa, Shinya Oishia, Hirokazu Tamamuraa, Akira Otakaa, Jean-Marc Navenotb, James R. Broachc, Stephen C. Peiperb and Nobutaka Fujiia, Corresponding Author Contact Information, E-mail The Corresponding Author

aGraduate School of Pharmaceutical Sciences of Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

bDepartment of Pathology and Immunotherapy Center, Medical College of Georgia, Augusta, GA 30912, USA

cDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544, USA

Received 22 August 2005;

revised 8 September 2005;

accepted 12 September 2005.

Available online 18 October 2005.


Abstract

Metastin has been identified as a metastasis suppressor gene product that mediates its function through a G protein coupled receptor, GPR54. To refine insight into the critical pharmacophore for the activation of GPR54, we have conducted alanine and d-amino acid scanning on a biologically active metastin fragment (45-54). Based on these data and structures of peptides previously reported to activate GPR54, a series of shortened metastin (45-54) derivatives were synthesized and tested for the ability to induce GPR54 signaling. These biological experiments were performed in yeast containing human GPR54 that was coupled to the pheromone response pathway and a pheromone responsive lacZ reporter gene. Compounds 32, 33, and 39, which possess an N-terminal basic group and a C-terminal RW-amide motif, were strong agonists, similar to the level of metastin. This may provide an approach to reverse the pro-metastatic effect of metastin deletion in multiple malignant tumors.

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Figure 5. GPR54-agonistic activities of metastin and metastin shortened derivatives 3142 in lacZ reporter gene assay on yeast.

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Table 1.
EC50 values of several invertebrate neuropeptides for human GPR54 reported by Clements et al.

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Corresponding Author Contact InformationCorresponding author. Tel.: +81 75 753 4551; fax: +81 75 753 4570.

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Bioorganic & Medicinal Chemistry Letters Volume 16, Issue 1, 1 January 2006, Pages 134-137           Abstract Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity   References and further reading may be available for this article. To view references and further reading you must purchase…
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