title: ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth.
abstract: Bombesin receptor subtype (BRS)-3 is a G protein coupled receptor (GPCR) for the bombesin (BB)-family of peptides. BRS-3 is an orphan GPCR and little is known of its physiological role due to the lack of specific agonists 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 but not 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 inhibited specific (125)I-BA1 (DTyr-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2)BB(6-14) binding to NCI-H1299 lung cancer cells stably transfected with BRS-3 with IC50 values of 4.8 and >100μM, respectively. In contrast, ML-18 bound with lower affinity to the GRPR and NMBR with IC50 values of 16 and >100μM, respectively. ML-18 (16μM), but not its enantiomer EMY-98, inhibited the ability of 10nM BA1 to elevate cytosolic Ca(2+) in a reversible manner using lung cancer cells loaded with FURA2-AM. ML-18 (16μM), but not EMY-98, inhibited the ability of 100nM BA1 to cause tyrosine phosphorylation of the EGFR and ERK in lung cancer cells. 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.
authors.affiliation: Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, MD 20892, USA. Electronic address: moodyt@mail.nih.gov.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Mantey
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Moreno
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, USA.
authors.forename: Taichi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Dipartimento di Farmacia, Scienze del Farmaco, Universita degli Studi di Bari "A. Moro", Bari, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.affiliation: Dipartimento di Farmacia, Scienze del Farmaco, Universita degli Studi di Bari "A. Moro", Bari, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, Bethesda, MD 20892, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jensen
mesh_terms: D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*
chemical_list: C000604712:3-(1H-indol-3-yl)-N-((1-(4-methoxyphenyl)cyclohexyl)methyl)-2-((4-nitrophenyl)carbamoylamino)propanamide; D007211:Indoles; D010671:Phenylurea Compounds; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium
keywords: Bombesin receptor subtype 3; Lung cancer; Nonpeptide antagonist; Proliferation