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AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists

While peptide antagonists for the gastrin-releasing peptide receptor (BB(2)R), neuromedin B receptor (BB(1)R), and bombesin (BB) receptor subtype-3 (BRS-3) exist, there is a need to develop non-peptide small molecule inhibitors for all three BBR. The BB agonist (BA)1 binds with high affinity to the...

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Detalles Bibliográficos
Autores principales: Moody, Terry W., Tashakkori, Nicole, Mantey, Samuel A., Moreno, Paola, Ramos-Alvarez, Irene, Leopoldo, Marcello, Jensen, Robert T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519534/
https://www.ncbi.nlm.nih.gov/pubmed/28785244
http://dx.doi.org/10.3389/fendo.2017.00176
Descripción
Sumario:While peptide antagonists for the gastrin-releasing peptide receptor (BB(2)R), neuromedin B receptor (BB(1)R), and bombesin (BB) receptor subtype-3 (BRS-3) exist, there is a need to develop non-peptide small molecule inhibitors for all three BBR. The BB agonist (BA)1 binds with high affinity to the BB(1)R, BB(2)R, and BRS-3. In this communication, small molecule BBR antagonists were evaluated using human lung cancer cells. AM-37 and ST-36 inhibited binding to human BB(1)R, BB(2)R, and BRS-3 with similar affinity (Ki = 1.4–10.8 µM). AM-13 and AM-14 were approximately an order of magnitude less potent than AM-37 and ST-36. The ability of BA1 to elevate cytosolic Ca(2+) in human lung cancer cells transfected with BB(1)R, BB(2)R, and BRS-3 was antagonized by AM-37 and ST-36. BA1 increased tyrosine phosphorylation of the EGFR and ERK in lung cancer cells, which was blocked by AM-37 and ST-36. AM-37 and ST-36 reduced the growth of lung cancer cells that have BBR. The results indicate that AM-37 and ST-36 function as small molecule BB receptor antagonists.