Bombesin receptor subtype (BRS)-3 is a G protein coupled receptor (GPCR) for the bombesin (BB)-familyof peptides. BRS-3 is an orphan GPCR and little is known of its physiological role due to the lack of specificagonists and antagonists. PD168368 is a nonpeptide antagonist for the neuromedin B (NMB) receptor (R)whereas PD176252 is a nonpeptide antagonist for the gastrin releasing peptide (GRP) R and NMBR butnot BRS-3. Here nonpeptide analogs of PD176252 e.g. the S-enantiomer ML-18, and the R-enantiomer,EMY-98, were investigated as BRS-3 antagonists using lung cancer cells. ML-18 and EMY-98 inhibitedspecific125I-BA1 (DTyr-Gln-Trp-Ala-Val-Ala-His-Phe-Nle-NH2)BB6-14binding to NCI-H1299 lung cancercells stably transfected with BRS-3 with IC50values of 4.8 and >100 M, respectively. In contrast, ML-18bound with lower affinity to the GRPR and NMBR with IC50values of 16 and >100 M, respectively. ML-18(16 M), but not its enantiomer EMY-98, inhibited the ability of 10 nM BA1 to elevate cytosolic Ca2+ina reversible manner using lung cancer cells loaded with FURA2-AM. ML-18 (16 M), but not EMY-98,inhibited the ability of 100 nM BA1 to cause tyrosine phosphorylation of the EGFR and ERK in lung cancercells. ML-18 but not EMY-98 inhibited the proliferation of lung cancer cells. The results indicate that ML-18 is a nonpeptide BRS-3 antagonist that should serve as a template to improve potency and selectivity.

ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth.

LACIVITA, ENZA;LEOPOLDO, Marcello;
2015

Abstract

Bombesin receptor subtype (BRS)-3 is a G protein coupled receptor (GPCR) for the bombesin (BB)-familyof peptides. BRS-3 is an orphan GPCR and little is known of its physiological role due to the lack of specificagonists and antagonists. PD168368 is a nonpeptide antagonist for the neuromedin B (NMB) receptor (R)whereas PD176252 is a nonpeptide antagonist for the gastrin releasing peptide (GRP) R and NMBR butnot BRS-3. Here nonpeptide analogs of PD176252 e.g. the S-enantiomer ML-18, and the R-enantiomer,EMY-98, were investigated as BRS-3 antagonists using lung cancer cells. ML-18 and EMY-98 inhibitedspecific125I-BA1 (DTyr-Gln-Trp-Ala-Val-Ala-His-Phe-Nle-NH2)BB6-14binding to NCI-H1299 lung cancercells stably transfected with BRS-3 with IC50values of 4.8 and >100 M, respectively. In contrast, ML-18bound with lower affinity to the GRPR and NMBR with IC50values of 16 and >100 M, respectively. ML-18(16 M), but not its enantiomer EMY-98, inhibited the ability of 10 nM BA1 to elevate cytosolic Ca2+ina reversible manner using lung cancer cells loaded with FURA2-AM. ML-18 (16 M), but not EMY-98,inhibited the ability of 100 nM BA1 to cause tyrosine phosphorylation of the EGFR and ERK in lung cancercells. ML-18 but not EMY-98 inhibited the proliferation of lung cancer cells. The results indicate that ML-18 is a nonpeptide BRS-3 antagonist that should serve as a template to improve potency and selectivity.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/8039
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