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1.
J Med Chem ; 63(5): 2358-2371, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589041

RESUMO

G-protein-coupled receptors like the human Y1 receptor (hY1R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY1R-preferring ligand [F7,P34]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY1R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.

2.
J Org Chem ; 85(3): 1446-1457, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31813224

RESUMO

Boron neutron capture therapy (BNCT) allows the selective elimination of malignant tumor cells without affecting healthy tissue. Although this binary radiotherapy approach has been known for decades, BNCT failed to reach the daily clinics to date. One of the reasons is the lack of selective boron delivery agents. Using boron loaded peptide conjugates, which address G protein-coupled receptors overexpressed on tumor cells allow the intracellular accumulation of boron. The gastrin-releasing peptide receptor (GRPR) is a well-known target in cancer diagnosis and can potentially be used for BNCT. Here, we present the successful introduction of multiple bis-deoxygalactosyl-carborane building blocks to the GRPR-selective ligand [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) (sBB2L) generating peptide conjugates with up to 80 boron atoms per molecule. Receptor activation was retained, metabolic stability was increased, and uptake into PC3 cells was proven without showing any intrinsic cytotoxicity. Furthermore, undesired uptake into liver cells was suppressed by using l-deoxygalactosyl modified carborane building blocks. Due to its high boron loading and excellent GRPR selectivity, this conjugate can be considered as a promising boron delivery agent for BNCT.

3.
Dalton Trans ; 49(1): 57-69, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31808482

RESUMO

Introduction of a bis(isopropylidene)-protected galactopyranosyl moiety in s-triazine-based boron-rich carboxylic acids and amines results in soluble and suitable coupling partners for tumour-selective biomolecules with applications as selective agents for boron neutron capture therapy (BNCT). Bearing either a carboxylic acid or primary amine as a functional group, these compounds are highly versatile and thus largely extend the possible coupling strategies with suitable biomolecules. Modification of the gastrin-releasing peptide receptor (GRPR) selective agonist [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) with the carboxylic acid derivative yielded a bioconjugate with an optimal receptor activation and internalisation profile. This demonstrates the great potential of this approach for the development of novel boron delivery agents.

4.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509949

RESUMO

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as α-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.


Assuntos
Terapia por Captura de Nêutron de Boro , Boro/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Boro/química , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Ésteres/química , Glicina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Estrutura Molecular , Neoplasias/patologia , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Triazinas/química , Triazinas/farmacologia
5.
Dalton Trans ; 48(29): 10834-10844, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31246208

RESUMO

Based on a modular combination of s-triazine, the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12) and commercially available carboxylic acids, namely thioglycolic acid, glycine, and Nα-Boc-l-lysine, several carboxylic acid derivatives were synthesised and fully characterised. The thioglycolic acid derivative was introduced into a peptide hormone by solid phase peptide synthesis. High activity and selective internalisation into peptide receptor-expressing cells was observed. With a very high boron content of twenty boron atoms, these derivatives are interesting as selective Boron Neutron Capture Therapy (BNCT) agents.

6.
Chem Commun (Camb) ; 55(19): 2821-2824, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30762062

RESUMO

Previous studies have led to opposing hypotheses about the requirement of intermolecular disulfide exchange in the binding of the iron regulatory peptide hepcidin to its receptor ferroportin. To clarify this issue, we used the diaminodiacid approach to replace the disulfide bonds in hepcidin with non-reducible thioether bonds. Our results implied that disulfide exchange is not required for the interaction between hepcidin and ferroportin. This theory is further supported by our development of biologically active minihepcidins that do not show activity dependence on cysteine.

7.
J Pept Sci ; 25(3): e3147, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30680847

RESUMO

Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM-1 receptor (AM1 R). A disulfide-bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/t-Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam-based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether-based mimetics to be well accepted with full AM1 R activity. While a reduced selectivity over the calcitonin gene-related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild-type-like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1 R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM.


Assuntos
Adrenomedulina/química , Adrenomedulina/farmacologia , Dissulfetos/química , Receptores de Adrenomedulina/agonistas , Receptores de Adrenomedulina/metabolismo , Adrenomedulina/síntese química , Dissulfetos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
8.
J Pept Sci ; 24(10): e3119, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30168238

RESUMO

Boron neutron capture therapy (BNCT) is a binary cancer therapy, which combines the biochemical targeting of a boron-containing drug with the regional localization of radiation treatment. Although the concept of BNCT has been known for decades, the selective delivery of boron into tumor cells remains challenging. G protein-coupled receptors that are overexpressed on cancer cells in combination with peptidic ligands can be potentially used as shuttle system for a tumor-directed boron uptake. In this study, we present the generation of short, boron-rich peptide conjugates that target the ghrelin receptor. Expression of the ghrelin receptor on various cancer cells makes it a viable target for BNCT. We designed a novel hexapeptide super-agonist that was modified with different specifically synthesized carborane monoclusters and tested for ghrelin receptor activation. A meta-carborane building block with a mercaptoacetic acid linker was found to be optimal for peptide modification, owing to its chemical stability and a suitable activation efficacy of the conjugate. The versatility of this carborane for the development of peptidic boron delivery agents was further demonstrated by the generation of highly potent, boron-loaded conjugates using the backbone of the known ghrelin receptor ligands growth hormone releasing peptide 6 and Ipamorelin.


Assuntos
Boro/farmacologia , Peptídeos/síntese química , Receptores de Grelina/agonistas , Boro/química , Terapia por Captura de Nêutron de Boro , Portadores de Fármacos , Células HEK293 , Humanos , Oligopeptídeos/química , Peptídeos/química
9.
ChemMedChem ; 13(17): 1797-1805, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-29979487

RESUMO

Adrenomedullin (ADM) is a peptide hormone of the calcitonin gene-related peptide (CGRP) family. It is involved in the regulation of cardiovascular processes such as angiogenesis, vasodilation, and the reduction of oxidative stress. ADM mediates its effects by activation of the ADM-1 and -2 receptors (AM1 R/AM2 R), but also activates the CGRP receptor (CGRPR) with reduced potency. It binds to the extracellular domains of the receptors with its C-terminal binding motif (residues 41-52). The activation motif, consisting of a disulfide-bonded ring structure (residues 16-21) and an adjacent helix (residues 22-30), binds to the transmembrane region and stabilizes the receptor conformation in the active state. While it was shown that the binding motif of ADM guides AM1 R selectivity, there is little information on the activation motif itself. Here, we demonstrate that Thr22 of ADM contributes to the selectivity. By using solid-phase peptide synthesis and cAMP-based signal transduction, we studied the effects of analogues in the activation motif of ADM on AM1 R and CGRPR activity. Our results indicate that Thr22 terminates the α-helix and orients the ring segment by hydrogen bonding. Using olefin stapling, we showed that the α-helical arrangement of the ring segment leads to decreased AM1 R activity, but does not affect CGRPR activation. These results demonstrate that the conformation of the ring segment of ADM has a strong impact on the selectivity within the receptor system.


Assuntos
Adrenomedulina/farmacologia , Proteína Semelhante a Receptor de Calcitonina/antagonistas & inibidores , Cardiotônicos/farmacologia , Treonina/química , Adrenomedulina/química , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Cardiotônicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
10.
ChemMedChem ; 11(21): 2378-2384, 2016 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-27558296

RESUMO

The apelin ligand receptor system is an important target to develop treatment strategies for cardiovascular diseases. Although apelin exhibits strong inotropic effects, its pharmaceutical application is limited because no agonist with suitable properties is available. On the one hand, peptide ligands are too instable, and on the other hand, small-molecule agonists show only low potency. This study describes the development of apelin (APJ) receptor agonists with not only high activity but also metabolic stability. Several strategies including capping of termini, insertion of unnatural amino acids, cyclization, and lipidation were analyzed. Peptide activity was tested using a Ca2+ -mobilization assay and the degradation of selected analogues was analyzed in rat plasma. The best results were obtained by N-terminal lipidation of a 13-mer apelin derivative. This analogue displayed a half-life of 29 h in rat plasma, compared with 0.025 h for the wild-type peptide. Furthermore, in vivo pharmacokinetics revealed a clearance of 0.049 L h-1 kg-1 and a half-life of 0.36 h. In summary, amino acid substitution and fatty acid modification resulted in a potent and 1000-fold more stable peptide that exhibits high pharmaceutical potential.

11.
J Med Chem ; 59(12): 5695-705, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27166982

RESUMO

The 52 amino acid peptide hormone adrenomedullin (ADM) plays a major role in the development and regulation of the cardiovascular and lymphatic system and has therefore gained significant interest for clinical applications. Because adrenomedullin exhibits low metabolic stability, enhancement of the plasma half-life is essential for peptide-based drug design. Fluorescently labeled ADM analogues synthesized by Fmoc/t-Bu solid phase peptide synthesis were used to analyze their enzymatic degradation and specific fragmentation pattern in human blood plasma. The determination of important cleavage sites allowed the development of selectively modified peptides in a rational approach. By combination of palmitoylation, lactam-bridging, and Nα-methylation, ADM analogues protected from enzymatic cleavage in human blood were developed and revealed an explicitly elongated half-life of 5 days in comparison to the wild-type in vitro. This triple-modification did not alter the selectivity of the analogues at the AM1 receptor, highlighting their potential for therapeutic applications.


Assuntos
Adrenomedulina/metabolismo , Adrenomedulina/sangue , Adrenomedulina/química , Adrenomedulina/farmacologia , Células Cultivadas , Estabilidade de Medicamentos , Células HEK293 , Meia-Vida , Humanos , Estrutura Molecular , Receptores de Adrenomedulina/agonistas , Receptores de Adrenomedulina/metabolismo , Relação Estrutura-Atividade
12.
J Pept Sci ; 21(12): 905-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26767744

RESUMO

The human adrenomedullin (ADM) is a 52 amino acid peptide hormone belonging to the calcitonin family of peptides, which plays a major role in the development and regulation of cardiovascular and lymphatic systems. For potential use in clinical applications, we aimed to investigate the fate of the peptide ligand after binding and activation of the adrenomedullin receptor (AM1), a heterodimer consisting of the calcitonin receptor-like receptor (CLR), a G protein-coupled receptor, associated with the receptor activity-modifying protein 2 (RAMP2). Full length and N-terminally shortened ADM peptides were synthesized using Fmoc/tBu solid phase peptide synthesis and site-specifically labeled with the fluorophore carboxytetramethylrhodamine (Tam) either by amide bond formation or copper(I)-catalyzed azide alkyne cycloaddition. For the first time, Tam-labeled ligands allowed the observation of co-internalization of the whole ligand-receptor complex in living cells co-transfected with fluorescent fusion proteins of CLR and RAMP2. Application of a fluorescent probe to track lysosomal compartments revealed that ADM together with the CLR/RAMP2-complex is routed to the degradative pathway. Moreover, we found that the N-terminus of ADM is not a crucial component of the peptide sequence in terms of AM1 internalization behavior.


Assuntos
Adrenomedulina/química , Peptídeos/síntese química , Peptídeos/metabolismo , Receptores de Adrenomedulina/metabolismo , Adrenomedulina/metabolismo , Proteína Semelhante a Receptor de Calcitonina/química , Proteína Semelhante a Receptor de Calcitonina/genética , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Corantes Fluorescentes/química , Células HEK293 , Humanos , Lisossomos/ultraestrutura , Peptídeos/química , Transporte Proteico , Proteína 2 Modificadora da Atividade de Receptores/química , Proteína 2 Modificadora da Atividade de Receptores/genética , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Receptores de Adrenomedulina/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Rodaminas/química
13.
Antiviral Res ; 95(2): 182-91, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22580131

RESUMO

The RNA-dependent RNA polymerase NS5B of the hepatitis C virus (HCV) has emerged as one of the key targets for antiviral drug discovery. Here we describe a novel non-nucleoside inhibitor (NNI) chemotype identified by screening: The substituted N-phenylbenzenesulphonamides (SPBS) which showed reversible inhibition of NS5B from HCV genotype 1b with IC(50) values up to 40 nM. Based on the decreased inhibitory activity against a recombinant NS5B protein carrying the mutation L419M or M423T we assumed that the SPBS inhibitors bind to the thumb site II which has already been described as the allosteric binding site for the NNI carboxy thiophene. The postulated binding site was consequently confirmed by solving two co-crystal structures of NS5B in complex with SPBS analogues at 2.3 and 2.2Å resolutions. The inhibitors are hydrogen-bonded to the main chain Ser476 and Tyr477 and to the side chain of Arg501. In addition, the inhibitors displayed van der Waals interactions with several residues of the hydrophobic binding pocket Leu419, Ile482, Leu497, Met423 and Trp528. Notably, the two SPBS analogues reported here revealed significant differences in addressing the NH-group of the main chain Tyr477 by hydrogen-bonds, water-mediated or directly, which provoked a shift of the carboxyphenyl group of the inhibitors towards the His475 position for the water-mediated binding mode. Interestingly, the differences observed in the binding mode led to a different cross resistance profile at positions M423 and I482. Using a panel of 38 individual NS5B proteins derived from different HCV genotypes, we could demonstrate inhibitory activity of the SPBS against polymerases from HCV genotypes 1a and 1b whereas the inhibitor class failed to inhibit any of the non-genotype 1 polymerases efficiently. Furthermore we demonstrated initial antiviral activity for SPBS against the subgenomic replicons of HCV genotypes 1a and 1b, respectively, and no considerable cytotoxic potential against a panel of ten different cell types.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Hepatócitos/virologia , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
14.
Circulation ; 118(20): 2081-90, 2008 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-18955668

RESUMO

BACKGROUND: Inhibition of tyrosine kinases, including platelet-derived growth factor receptor, can reduce pulmonary arterial pressure in experimental and clinical pulmonary hypertension. We hypothesized that inhibition of the serine/threonine kinases Raf-1 (also termed c-Raf) and b-Raf in addition to inhibition of tyrosine kinases effectively controls pulmonary vascular and right heart remodeling in pulmonary hypertension. METHODS AND RESULTS: We investigated the effects of the novel multikinase inhibitor sorafenib, which inhibits tyrosine kinases as well as serine/threonine kinases, in comparison to imatinib, a tyrosine kinase inhibitor, on hemodynamics, pulmonary and right ventricular (RV) remodeling, and downstream signaling in experimental pulmonary hypertension. Fourteen days after monocrotaline injection, male rats were treated orally for another 14 days with sorafenib (10 mg/kg per day), imatinib (50 mg/kg per day), or vehicle (n=12 to 16 per group). RV systolic pressure was decreased to 35.0+/-1.5 mm Hg by sorafenib and to 54.0+/-4.4 mm Hg by imatinib compared with placebo (82.9+/-6.0 mm Hg). In parallel, both sorafenib and imatinib reduced RV hypertrophy and pulmonary arterial muscularization. The effects of sorafenib on RV systolic pressure and RV mass were significantly greater than those of imatinib. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of the downstream ERK1/2 signaling pathway in RV myocardium and the lungs. In addition, sorafenib but not imatinib antagonized vasopressin-induced hypertrophy of the cardiomyoblast cell line H9c2. CONCLUSIONS: The multikinase inhibitor sorafenib prevents pulmonary remodeling and improves cardiac and pulmonary function in experimental pulmonary hypertension. Sorafenib exerts direct myocardial antihypertrophic effects, which appear to be mediated via inhibition of the Raf kinase pathway. The combined inhibition of tyrosine and serine/threonine kinases may provide an option to treat pulmonary arterial hypertension and associated right heart remodeling.


Assuntos
Benzenossulfonatos/farmacologia , Hipertensão Pulmonar/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Quinases raf/antagonistas & inibidores , Animais , Benzamidas , Pressão Sanguínea/efeitos dos fármacos , Progressão da Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Ventrículos do Coração , Mesilato de Imatinib , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Niacinamida/análogos & derivados , Compostos de Fenilureia , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sorafenibe
15.
J Pharmacol Exp Ther ; 321(2): 716-25, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17308038

RESUMO

The relative contribution of alpha4beta2, alpha7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the alpha7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (ABBF). ABBF bound to alpha7 nAChR in rat brain membranes (Ki=62 nM) and to recombinant human 5-hydroxytryptamine (5-HT)3 receptors (Ki=60 nM). ABBF was a potent agonist at the recombinant rat and human alpha7 nAChR expressed in Xenopus oocytes, but it did not show agonist activity at other nAChR subtypes. ABBF acted as an antagonist of the 5-HT3 receptor and alpha3beta4, alpha4beta2, and muscle nAChRs (at higher concentrations). ABBF improved social recognition memory in rats (0.3-1 mg/kg p.o.). This improvement was blocked by intracerebroventricular administration of the alpha7 nAChR antagonist methyllycaconitine at 10 microg, indicating that it is mediated by alpha7 nAChR agonism. In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3-1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3-30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the alpha7 nAChR and that selective alpha7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that alpha7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.


Assuntos
Benzofuranos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Memória/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Quinuclidinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Transtornos Cognitivos/tratamento farmacológico , Comportamento Exploratório/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Ratos Wistar , Receptor Nicotínico de Acetilcolina alfa7
16.
Cancer Res ; 64(19): 7099-109, 2004 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15466206

RESUMO

The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.


Assuntos
Benzenossulfonatos/farmacologia , MAP Quinase Quinase Quinase 1 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/enzimologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-raf/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Med Chem Lett ; 14(3): 783-6, 2004 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-14741289

RESUMO

Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.


Assuntos
Inibidores Enzimáticos/farmacologia , MAP Quinase Quinase Quinase 1 , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Amidas/síntese química , Amidas/farmacologia , Baculoviridae/genética , Inibidores Enzimáticos/síntese química , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Solubilidade , Relação Estrutura-Atividade , Ureia/síntese química
18.
Bioorg Med Chem ; 10(12): 3905-13, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12413842

RESUMO

Several types of furanomycin analogues were synthesized and investigated with respect to their antibacterial activity. Two different synthetic pathways were developed, based on aldol reactions/ring closing metathesis and an ester enolate Claisen rearrangement. Only the natural product and its desmethyl derivative showed antibacterial activity, pointing towards a narrow structure-activity relationship.


Assuntos
Aminoácidos/síntese química , Antibacterianos/síntese química , Aminoácidos/farmacologia , Antibacterianos/farmacologia , Eubacterium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estereoisomerismo , Relação Estrutura-Atividade
19.
Curr Pharm Des ; 8(25): 2269-78, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12369855

RESUMO

Raf kinase, an enzyme which acts downstream in the Ras signaling pathway, is involved in cancerous cell proliferation. Thus, small molecule inhibitors of Raf kinase activity may be important agents for the treatment of cancer. A novel class of Raf-1 inhibitors was discovered, using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials. The present review summarizes the medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Animais , Divisão Celular/efeitos dos fármacos , Desenho de Fármacos , Humanos , Relação Estrutura-Atividade
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