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Robert T. Jensen - One of the best experts on this subject based on the ideXlab platform.

  • Bombesin Receptor family activation and cns neural tumors review of evidence supporting possible role for novel targeted therapy
    Frontiers in Endocrinology, 2021
    Co-Authors: Terry W Moody, Irene Ramosalvarez, Samuel A Mantey, Lingaku Lee, Tatiana Iordanskaia, Robert T. Jensen
    Abstract:

    G-protein-coupled Receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-Receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

  • neuropeptide Bombesin Receptor activation stimulates growth of lung cancer cells through her3 with a mapk dependent mechanism
    Biochimica et Biophysica Acta, 2020
    Co-Authors: Lingaku Lee, Samuel A Mantey, Irene Ramosalvarez, Terry W Moody, Robert T. Jensen
    Abstract:

    Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-Receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled Receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of Bombesin Receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.

  • a possible new target in lung cancer cells the orphan Receptor Bombesin Receptor subtype 3
    Peptides, 2018
    Co-Authors: Paola Moreno, Irene Ramosalvarez, Samuel A Mantey, Terry W Moody, Suk Hee Lee, Robert T. Jensen
    Abstract:

    Human Bombesin Receptors, GRPR and NMBR, are two of the most frequently overexpressed G-protein-coupled-Receptors by lung-cancers. Recently, GRPR/NMBR are receiving considerable attention because they act as growth factor Receptors often in an autocrine manner in different lung-cancers, affect tumor angiogenesis, their inhibition increases the cytotoxic potency of tyrosine-kinase inhibitors reducing lung-cancer cellular resistance/survival and their overexpression can be used for sensitive tumor localization as well as to target cytotoxic agents to the cancer. The orphan BRS-3-Receptor, because of homology is classified as a Bombesin Receptor but has received little attention, despite the fact that it is also reported in a number of studies in lung-cancer cells and has growth effects in these cells. To address its potential importance, in this study, we examined the frequency/relative quantitative expression of human BRS-3 compared to GRPR/NMBR and the effects of its activation on cell-signaling/growth in 13 different human lung-cancer cell-lines. Our results showed that BRS-3 Receptor is expressed in 92% of the cell-lines and that it is functional in these cells, because its activation stimulates phospholipase-C with breakdown of phosphoinositides and changes in cytosolic calcium, stimulates ERK/MAPK and stimulates cell growth by EGFR transactivation in some, but not all, the lung-cancer cell-lines. These results suggest that human BRS-3, similar to GRPR/NMBR, is frequently ectopically-expressed by lung-cancer cells in which, it is functional, affecting cell signaling/growth. These results suggest that similar to GRPR/NMBR, BRS-3 should receive increased attention as possible approach for the development of novel treatments and/or diagnosis in lung-cancer.

  • am 37 and st 36 are small molecule Bombesin Receptor antagonists
    Frontiers in Endocrinology, 2017
    Co-Authors: Terry W Moody, Irene Ramosalvarez, Samuel A Mantey, Paola Moreno, Nicole Tashakkori, Marcello Leopoldo, Robert T. Jensen
    Abstract:

    While peptide antagonists for the gastrin releasing peptide Receptor (BB2R), neuromedin B Receptor (BB1R) and Bombesin Receptor subtype-3 (BRS-3) exist, there is a need to develop nonpeptide small molecule inhibitors for all three BBR. The Bombesin agonist (BA)1 binds with high affinity to the BB1R, BB2R 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 BB2R, BB1R and BRS-3 with similar affinity (Ki = 1.4-10.8 uM). 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 Ca2+ in human lung cancer cells transfected with BB1R, BB2R 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 which have BBR. The results indicated that AM-37 and ST-36 function as small molecule BBR antagonists.

  • AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists
    Frontiers Media S.A., 2017
    Co-Authors: Terry W Moody, Samuel A Mantey, Paola Moreno, Nicole Tashakkori, Marcello Leopoldo, Irene Ramos-alvarez, Robert T. Jensen
    Abstract:

    While peptide antagonists for the gastrin-releasing peptide Receptor (BB2R), neuromedin B Receptor (BB1R), 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 BB1R, BB2R, 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 BB1R, BB2R, 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 Ca2+ in human lung cancer cells transfected with BB1R, BB2R, 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

Samuel A Mantey - One of the best experts on this subject based on the ideXlab platform.

  • Bombesin Receptor family activation and cns neural tumors review of evidence supporting possible role for novel targeted therapy
    Frontiers in Endocrinology, 2021
    Co-Authors: Terry W Moody, Irene Ramosalvarez, Samuel A Mantey, Lingaku Lee, Tatiana Iordanskaia, Robert T. Jensen
    Abstract:

    G-protein-coupled Receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-Receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

  • neuropeptide Bombesin Receptor activation stimulates growth of lung cancer cells through her3 with a mapk dependent mechanism
    Biochimica et Biophysica Acta, 2020
    Co-Authors: Lingaku Lee, Samuel A Mantey, Irene Ramosalvarez, Terry W Moody, Robert T. Jensen
    Abstract:

    Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-Receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled Receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of Bombesin Receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.

  • a possible new target in lung cancer cells the orphan Receptor Bombesin Receptor subtype 3
    Peptides, 2018
    Co-Authors: Paola Moreno, Irene Ramosalvarez, Samuel A Mantey, Terry W Moody, Suk Hee Lee, Robert T. Jensen
    Abstract:

    Human Bombesin Receptors, GRPR and NMBR, are two of the most frequently overexpressed G-protein-coupled-Receptors by lung-cancers. Recently, GRPR/NMBR are receiving considerable attention because they act as growth factor Receptors often in an autocrine manner in different lung-cancers, affect tumor angiogenesis, their inhibition increases the cytotoxic potency of tyrosine-kinase inhibitors reducing lung-cancer cellular resistance/survival and their overexpression can be used for sensitive tumor localization as well as to target cytotoxic agents to the cancer. The orphan BRS-3-Receptor, because of homology is classified as a Bombesin Receptor but has received little attention, despite the fact that it is also reported in a number of studies in lung-cancer cells and has growth effects in these cells. To address its potential importance, in this study, we examined the frequency/relative quantitative expression of human BRS-3 compared to GRPR/NMBR and the effects of its activation on cell-signaling/growth in 13 different human lung-cancer cell-lines. Our results showed that BRS-3 Receptor is expressed in 92% of the cell-lines and that it is functional in these cells, because its activation stimulates phospholipase-C with breakdown of phosphoinositides and changes in cytosolic calcium, stimulates ERK/MAPK and stimulates cell growth by EGFR transactivation in some, but not all, the lung-cancer cell-lines. These results suggest that human BRS-3, similar to GRPR/NMBR, is frequently ectopically-expressed by lung-cancer cells in which, it is functional, affecting cell signaling/growth. These results suggest that similar to GRPR/NMBR, BRS-3 should receive increased attention as possible approach for the development of novel treatments and/or diagnosis in lung-cancer.

  • am 37 and st 36 are small molecule Bombesin Receptor antagonists
    Frontiers in Endocrinology, 2017
    Co-Authors: Terry W Moody, Irene Ramosalvarez, Samuel A Mantey, Paola Moreno, Nicole Tashakkori, Marcello Leopoldo, Robert T. Jensen
    Abstract:

    While peptide antagonists for the gastrin releasing peptide Receptor (BB2R), neuromedin B Receptor (BB1R) and Bombesin Receptor subtype-3 (BRS-3) exist, there is a need to develop nonpeptide small molecule inhibitors for all three BBR. The Bombesin agonist (BA)1 binds with high affinity to the BB1R, BB2R 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 BB2R, BB1R and BRS-3 with similar affinity (Ki = 1.4-10.8 uM). 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 Ca2+ in human lung cancer cells transfected with BB1R, BB2R 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 which have BBR. The results indicated that AM-37 and ST-36 function as small molecule BBR antagonists.

  • AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists
    Frontiers Media S.A., 2017
    Co-Authors: Terry W Moody, Samuel A Mantey, Paola Moreno, Nicole Tashakkori, Marcello Leopoldo, Irene Ramos-alvarez, Robert T. Jensen
    Abstract:

    While peptide antagonists for the gastrin-releasing peptide Receptor (BB2R), neuromedin B Receptor (BB1R), 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 BB1R, BB2R, 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 BB1R, BB2R, 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 Ca2+ in human lung cancer cells transfected with BB1R, BB2R, 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

David H. Coy - One of the best experts on this subject based on the ideXlab platform.

  • 2004. Development of Bombesin analogs with conformationally restricted amino acid substitutions with enhanced selectivity for the orphan Receptor human Bombesin Receptor subtype 3
    2016
    Co-Authors: Samuel A Mantey, David H. Coy, Laurence K. Entsuah, Robert T. Jensen
    Abstract:

    The human Bombesin Receptor subtype 3 (hBRS-3) orphan recep-tor, which has a high homology to Bombesin (Bn) Receptors [gas-trin-releasing peptide (GRP) and neuromedin B (NMB) Receptors], is widely distributed in the rat central nervous system. Its natural ligand or role in physiology is unknown due to lack of selective ligands. Its target disruption leads to obesity, diabetes, and hy-pertension. A synthetic high-affinity agonist, [D-Tyr6,-Ala11,Phe13,Nle14]Bn(6-14), has been described, but it is nonse-lective for hBRS-3 over other Bn Receptors; however, substitution of (R)- or (S)-amino-3-phenylpropionic acid (Apa) for -Ala11 re-sulted in a modestly selective ligand. In the present study, we have attempted to develop a more selective hBRS-3 ligand by using two strategies: substitutions on phenyl ring of Apa11 and the substitution of other conformationally restricted amino acids int

  • comparative pharmacology of Bombesin Receptor subtype 3 nonpeptide agonist mk 5046 a universal peptide agonist and peptide antagonist bantag 1 for human Bombesin Receptors
    Journal of Pharmacology and Experimental Therapeutics, 2013
    Co-Authors: Paola Moreno, David H. Coy, Samuel A Mantey, Bernardo Nucheberenguer, Marc L. Reitman, Nieves Gonzalez, Robert T. Jensen
    Abstract:

    Bombesin-Receptor-subtype-3 (BRS-3) is an orphan G-protein-coupled Receptor of the Bombesin (Bn) family whose natural ligand is unknown and which does not bind any natural Bn-peptide with high affinity. It is present in the central nervous system, peripheral tissues, and tumors; however, its role in normal physiology/pathophysiology is largely unknown because of the lack of selective ligands. Recently, MK-5046 [(2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol] and Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate], a nonpeptide agonist and a peptide antagonist, respectively, for BRS-3 have been described, but there have been limited studies on their pharmacology. We studied MK-5046 and Bantag-1 interactions with human Bn-Receptors—human Bombesin Receptor subtype-3 (hBRS-3), gastrin-releasing peptide Receptor (GRP-R), and neuromedin B Receptor (NMB-R)—and compared them with the nonselective, peptide-agonist [d-Tyr6,βAla11,Phe13,Nle14]Bn-(6–14) (peptide #1). Receptor activation was detected by activation of phospholipase C (PLC), mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), paxillin, and Akt. In hBRS-3 cells, the relative affinities were Bantag-1 (1.3 nM) > peptide #1 (2 nM) > MK-5046 (37–160 nM) > GRP, NMB (>10 μM), and the binding-dose-inhibition curves were broad (>4 logs), with Hill coefficients differing significantly from unity. Curve-fitting demonstrated high-affinity (MK-5046, Ki = 0.08 nM) and low-affinity (MK-5046, Ki = 11–29 nM) binding sites. For PLC activation in hBRS-3 cells, the relative potencies were MK-5046 (0.02 nM) > peptide #1 (6 nM) > GRP, NMB, Bantag-1 (>10 μM), and MK-5046 had a biphasic dose response, whereas peptide #1 was monophasic. Bantag-1 was a specific hBRS-3-antagonist. In hBRS-3 cells, MK-5046 was a full agonist for activation of MAPK, FAK, Akt, and paxillin; however, it was a partial agonist for phospholipase A2 (PLA2) activation. The kinetics of activation/duration of action for PLC/MAPK activation of MK-5046 and peptide #1 differed, with peptide #1 causing more rapid stimulation; however, MK-5046 had more prolonged activity. Our study finds that MK-5046 and Bantag-1 have high affinity/selectivity for hBRS-3. The nonpeptide MK-5046 and peptide #1 agonists differ markedly in their Receptor coupling, ability to activate different signaling cascades, and kinetics/duration of action. These results show that their hBRS-3 Receptor activation is not always concordant and could lead to markedly different cellular responses.

  • the molecular basis for high affinity of a universal ligand for human Bombesin Receptor bnr family members
    Biochemical Pharmacology, 2012
    Co-Authors: Hirotsugu Uehara, David H. Coy, Samuel A Mantey, Nieves Gonzalez, Tatsuro Katsuno, Simon J Hocart, Tomoo Nakagawa, Robert T. Jensen
    Abstract:

    Abstract There is increased interest in the Bn-Receptor family because they are frequently over/ectopically expressed by tumors and thus useful as targets for imaging or Receptor-targeted-cytotoxicity. The synthetic Bn-analog, [ d -Tyr 6 , β-Ala 11 , Phe 13 , Nle 14 ]Bn(6–14) [Univ.Lig] has the unique property of having high affinity for all three human BNRs (GRPR, NMBR, BRS-3), and thus could be especially useful for this approach. However, the molecular basis of this property is unclear and is the subject of this study. To accomplish this, site-directed mutagenesis was used after identifying potentially important amino acids using sequence homology analysis of all BnRs with high affinity for Univ.Lig compared to the Cholecystokinin-Receptor (CCK A R), which has low affinity. Using various criteria 74 amino acids were identified and 101 mutations made in GRPR by changing each to those of CCK A R or to alanine. 22 GRPR mutations showed a significant decrease in affinity for Univ.Lig (>2-fold) with 2 in EC2[D97N, G112V], 1 in UTM6[Y284A], 2 in EC4[R287N, H300S] showing >10-fold decrease in Univ.Lig affinity. Additional mutations were made to explore the molecular basis for these changes. Our results show that high affinity for Univ.Lig by human Bn-Receptors requires positively charged amino acids in extracellular (EC)-domain 4 and to a lesser extent EC2 and EC3 suggesting charge-charge interactions may be particularly important for determining the general high affinity of this ligand. Furthermore, transmembrane amino acids particularly in UTM6 are important contributing both charge-charge interactions as well as interaction with a tyrosine residue in close proximity suggesting possible Receptor–peptide cation–π or H-bonding interactions are also important for determining its high affinity.

  • a selective human Bombesin Receptor subtype 3 peptide agonist mediates creb phosphorylation and transactivation
    Journal of Molecular Neuroscience, 2012
    Co-Authors: Xiaoqun Qin, David H. Coy, Christian H Weber
    Abstract:

    The native ligand for the G protein-coupled Bombesin Receptor subtype-3 (BRS-3) has currently not been identified. Studies in mice showed robust BRS-3 expression in the hypothalamic satiety centers, and genetic Receptor inactivation resulted in obesity, diabetes, and hypertension. BRS-3 was also detected in normal human pancreatic islet cells suggesting a critical role of BRS-3 in regulating energy metabolism and satiety via central and peripheral mechanisms of action. The cyclic AMP response element binding protein (CREB) is a main regulator of pancreatic β-cell gene expression required for glucose homeostasis and islet cell survival, and hypothalamic regulation of satiety. Therefore, in this study we examined whether agonist-dependent hBRS-3 stimulation mediates CREB activation. A selective hBRS-3 peptide agonist and two non-selective hBRS-3 peptide agonists were used to activate ectopically expressed hBRS-3. Stimulation with hBRS-3 peptide agonists resulted in transient calcium mobilization, whereby the selective peptide agonist acted exclusively via hBRS-3 but not through the gastrin-releasing peptide Receptor (GRP-R). A selective high-affinity GRP-R antagonist did not inhibit hBRS-3-mediated calcium signals. We also found time-dependent CREB phosphorylation in response to the selective hBRS-3 activation, which was abrogated by pretreatment with protein kinase A and protein kinase C inhibitors. Human BRS-3 agonists also stimulated CREB transactivation and resulted in modest increases of CRE-dependent gene transcription. These changes were significantly reduced after pretreatment with inhibitors of PKA, PKC, and MEK-1. Thus, our results suggest that hBRS-3 agonist-dependent signaling mediates CREB phosphorylation and transactivation through partially PKA, PKC, and MEK-1 pathways.

  • molecular basis for agonist selectivity and activation of the orphan Bombesin Receptor subtype 3 Receptor
    Journal of Pharmacology and Experimental Therapeutics, 2008
    Co-Authors: Nieves Gonzalez, David H. Coy, Samuel A Mantey, Simon J Hocart, Sergio Portalnunez, Tomoo Nakagawa, Enrique Zudaire, Robert T. Jensen
    Abstract:

    Bombesin Receptor subtype (BRS)-3, a G-protein-coupled orphan Receptor, shares 51% identity with the mammalian Bombesin (Bn) Receptor for gastrin-releasing peptide. There is increasing interest in BRS-3 because it is important in energy metabolism, glucose control, motility, and tumor growth. BRS-3 has low affinity for all Bn-related peptides; however, recently synthetic high-affinity agonists, [d-Tyr 6 /d-Phe 6 ,βAla 11 ,Phe 13 ,Nle 14 ]Bn-(6–14), were described, but they are nonselective for BRS-3 over other Bn Receptors. Based on these peptides, three BRS-3-selective ligands were developed: peptide 2, [d-Tyr 6 ( R )-3-amino-propionic acid 11 ,Phe 13 ,Nle 14 ]Bn(6–14); peptide 3, [d-Tyr 6 ,( R )-Apa 11 ,4Cl-Phe 13 ,Nle 14 ]Bn(6–14); and peptide 4, acetyl-Phe-Trp-Ala-His-(tBzl)-piperidine-3 carboxylic acid-Gly-Arg-NH 2 . Their molecular determinants of selectivity/high affinity for BRS-3 are unknown. To address this, we used a chimeric/site mutagenesis approach. Substitution of extracellular domain 2 (EC2) of BRS-3 by the comparable gastrin-releasing peptide Receptor (GRPR) domain decreased 26-, 4-, and 0-fold affinity for peptides 4, 3, and 2. Substitution of EC3 decreased affinity 4-, 11-, and 0-fold affinity for peptides 2 to 4. Ten-point mutations in the EC2 and adjacent transmembrane regions (TM2) 2 and 3 of BRS-3 were made. His107 (EC2-BRS-3) for lysine (H107K) (EC2-GRPR) decreased affinity (25- and 0-fold) for peptides 4 and 1; however, it could not be activated by either peptide. Its combination with Val101 (TM2), Gly112 (EC2), and Arg127 (TM3) resulted in complete loss-of-affinity of peptide 4. Receptor-modeling showed that each of these residues face inward and are within 4 A of the binding pocket. These results demonstrate that Val101, His107, Gly112, and Arg127 in the EC2/adjacent upper TMs of BRS-3 are critical for the high BRS3 selectivity of peptide 4. His107 in EC2 is essential for BRS-3 activation, suggesting amino-aromatic ligand/Receptor interactions with peptide 4 are critical for both binding and activation. Furthermore, these result demonstrate that even though these three BRS-3-selective agonists were developed from the same template peptide, [d-Phe 6 ,βAla 11 ,Phe 13 ,Nle 14 ]Bn-(6–14), their molecular determinants of selectivity/high affinity varied considerably.

Terry W Moody - One of the best experts on this subject based on the ideXlab platform.

  • Bombesin Receptor family activation and cns neural tumors review of evidence supporting possible role for novel targeted therapy
    Frontiers in Endocrinology, 2021
    Co-Authors: Terry W Moody, Irene Ramosalvarez, Samuel A Mantey, Lingaku Lee, Tatiana Iordanskaia, Robert T. Jensen
    Abstract:

    G-protein-coupled Receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-Receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

  • neuropeptide Bombesin Receptor activation stimulates growth of lung cancer cells through her3 with a mapk dependent mechanism
    Biochimica et Biophysica Acta, 2020
    Co-Authors: Lingaku Lee, Samuel A Mantey, Irene Ramosalvarez, Terry W Moody, Robert T. Jensen
    Abstract:

    Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-Receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled Receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of Bombesin Receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.

  • a possible new target in lung cancer cells the orphan Receptor Bombesin Receptor subtype 3
    Peptides, 2018
    Co-Authors: Paola Moreno, Irene Ramosalvarez, Samuel A Mantey, Terry W Moody, Suk Hee Lee, Robert T. Jensen
    Abstract:

    Human Bombesin Receptors, GRPR and NMBR, are two of the most frequently overexpressed G-protein-coupled-Receptors by lung-cancers. Recently, GRPR/NMBR are receiving considerable attention because they act as growth factor Receptors often in an autocrine manner in different lung-cancers, affect tumor angiogenesis, their inhibition increases the cytotoxic potency of tyrosine-kinase inhibitors reducing lung-cancer cellular resistance/survival and their overexpression can be used for sensitive tumor localization as well as to target cytotoxic agents to the cancer. The orphan BRS-3-Receptor, because of homology is classified as a Bombesin Receptor but has received little attention, despite the fact that it is also reported in a number of studies in lung-cancer cells and has growth effects in these cells. To address its potential importance, in this study, we examined the frequency/relative quantitative expression of human BRS-3 compared to GRPR/NMBR and the effects of its activation on cell-signaling/growth in 13 different human lung-cancer cell-lines. Our results showed that BRS-3 Receptor is expressed in 92% of the cell-lines and that it is functional in these cells, because its activation stimulates phospholipase-C with breakdown of phosphoinositides and changes in cytosolic calcium, stimulates ERK/MAPK and stimulates cell growth by EGFR transactivation in some, but not all, the lung-cancer cell-lines. These results suggest that human BRS-3, similar to GRPR/NMBR, is frequently ectopically-expressed by lung-cancer cells in which, it is functional, affecting cell signaling/growth. These results suggest that similar to GRPR/NMBR, BRS-3 should receive increased attention as possible approach for the development of novel treatments and/or diagnosis in lung-cancer.

  • am 37 and st 36 are small molecule Bombesin Receptor antagonists
    Frontiers in Endocrinology, 2017
    Co-Authors: Terry W Moody, Irene Ramosalvarez, Samuel A Mantey, Paola Moreno, Nicole Tashakkori, Marcello Leopoldo, Robert T. Jensen
    Abstract:

    While peptide antagonists for the gastrin releasing peptide Receptor (BB2R), neuromedin B Receptor (BB1R) and Bombesin Receptor subtype-3 (BRS-3) exist, there is a need to develop nonpeptide small molecule inhibitors for all three BBR. The Bombesin agonist (BA)1 binds with high affinity to the BB1R, BB2R 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 BB2R, BB1R and BRS-3 with similar affinity (Ki = 1.4-10.8 uM). 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 Ca2+ in human lung cancer cells transfected with BB1R, BB2R 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 which have BBR. The results indicated that AM-37 and ST-36 function as small molecule BBR antagonists.

  • AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists
    Frontiers Media S.A., 2017
    Co-Authors: Terry W Moody, Samuel A Mantey, Paola Moreno, Nicole Tashakkori, Marcello Leopoldo, Irene Ramos-alvarez, Robert T. Jensen
    Abstract:

    While peptide antagonists for the gastrin-releasing peptide Receptor (BB2R), neuromedin B Receptor (BB1R), 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 BB1R, BB2R, 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 BB1R, BB2R, 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 Ca2+ in human lung cancer cells transfected with BB1R, BB2R, 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

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  • the design and synthesis of potent selective benzodiazepine sulfonamide Bombesin Receptor subtype 3 brs 3 agonists with an increased barrier of atropisomerization
    Bioorganic & Medicinal Chemistry, 2012
    Co-Authors: Harry R Chobanian, Oksana C Palyha, Ping Liu, Thomas J Lanza, Yan Guo, Marc D Chioda, Linda Chang, Theresa M Kelly, Yanqing Kan, Xiaoming Guan
    Abstract:

    Bombesin Receptor subtype 3 (BRS-3) is an orphan G-protein coupled Receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective Bombesin Receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature.

  • Discovery of MK-7725, A Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity
    2012
    Co-Authors: Harry R Chobanian, Ping Liu, Yan Guo, Linda Chang, Theresa M Kelly, Yanqing Kan, Marc Chioda, Thomas J. Lanza, Oksana Palyha, Xiaoming Guan
    Abstract:

    Extensive structure–activity relationship studies of a series derived from atropisomer 1, a previously described chiral benzodiazepine sulfonamide series, led to a potent, brain penetrant and selective compound with excellent preclinical pharmacokinetic across species. We also describe the utilization of a high throughput mouse pharmacodynamic assay which allowed for expedient assessment of pharmacokinetic and brain distribution

  • Bombesin Receptor subtype 3 brs 3 regulates glucose stimulated insulin secretion in pancreatic islets across multiple species
    Endocrinology, 2011
    Co-Authors: Yue Feng, Marc L. Reitman, Xiaoming Guan, Joseph M Metzger, Yonghua Zhu, Kirstine Juhl, Bei B Zhang, Nancy A Thornberry, Yunping Zhou
    Abstract:

    Bombesin Receptor subtype-3 (BRS-3) regulates energy homeostasis, and BRS-3 agonism is being explored as a possible therapy for obesity. Here we study the role of BRS-3 in the regulation of glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. We quantified BRS-3 mRNA in pancreatic islets from multiple species and examined the acute effects of Bag-1, a selective BRS-3 agonist, on GSIS in mouse, rat, and human islets, and on oral glucose tolerance in mice. BRS-3 is highly expressed in human, mouse, rhesus, and dog (but not rat) pancreatic islets and in rodent insulinoma cell lines (INS-1 832/3 and MIN6). Silencing BRS-3 with small interfering RNA or pharmacological blockade with a BRS-3 antagonist, Bantag-1, reduced GSIS in 832/3 cells. In contrast, the BRS-3 agonist (Bag-1) increased GSIS in 832/3 and MIN6 cells. The augmentation of GSIS by Bag-1 was completely blocked by U73122, a phospholipase C inhibitor. Bag-1 also enhanced GSIS in islets isolated from wild-type, but not Brs3 knockout m...

  • antiobesity effect of mk 5046 a novel Bombesin Receptor subtype 3 agonist
    Journal of Pharmacology and Experimental Therapeutics, 2011
    Co-Authors: Xiaoming Guan, Joseph M Metzger, Liming Yang, Kate A Raustad, Shengping Wang, Stephanie K Spann, Jennifer A Kosinski, Lauren P Shearman, Terry D Faidley, Oksana C Palyha
    Abstract:

    Bombesin Receptor subtype-3 (BRS-3) is an orphan G protein-coupled Receptor implicated in the regulation of energy homeostasis. Here, we report the biologic effects of a highly optimized BRS-3 agonist, (2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol (MK-5046). Single oral doses of MK-5046 inhibited 2-h and overnight food intake and increased fasting metabolic rate in wild-type but not Brs3 knockout mice. Upon dosing for 14 days, MK-5046 at 25 mg · kg(-1) · day(-1) reduced body weight of diet-induced obese mouse by 9% compared with vehicle-dosed controls. In mice, 50% brain Receptor occupancy was achieved at a plasma concentration of 0.34 ± 0.23 μM. With chronic dosing, effects on metabolic rate, rather than food intake, seem to be the predominant mechanism for weight reduction by MK-5046. The compound also effectively reduced body weight in rats and caused modest increases in body temperature, heart rate, and blood pressure. These latter effects on temperature, heart rate, and blood pressure were transient in nature and desensitized with continued dosing. MK-5046 is the first BRS-3 agonist with properties suitable for use in larger mammals. In dogs, MK-5046 treatment produced statistically significant and persistent weight loss, which was initially accompanied by increases in body temperature and heart rate that abated with continued dosing. Our results demonstrate antiobesity efficacy for MK-5046 in rodents and dogs and further support BRS-3 agonism as a new approach to the treatment of obesity.

  • discovery of mk 7725 a potent selective Bombesin Receptor subtype 3 agonist for the treatment of obesity
    ACS Medicinal Chemistry Letters, 2011
    Co-Authors: Harry R Chobanian, Oksana C Palyha, Ping Liu, Thomas J Lanza, Yan Guo, Marc D Chioda, Linda Chang, Theresa M Kelly, Yanqing Kan, Xiaoming Guan
    Abstract:

    Extensive structure–activity relationship studies of a series derived from atropisomer 1, a previously described chiral benzodiazepine sulfonamide series, led to a potent, brain penetrant and selective compound with excellent preclinical pharmacokinetic across species. We also describe the utilization of a high throughput mouse pharmacodynamic assay which allowed for expedient assessment of pharmacokinetic and brain distribution.