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2.
Cancer Gene Ther ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426652

RESUMO

Angiogenesis, the formation of new blood vessels from preexisting ones, is crucial for tumor growth and metastatization, and is considered a promising therapeutic target. Unfortunately, drugs directed against a specific proangiogenic growth factor or receptor turned out to be of limited benefit for oncology patients, likely due to the high biochemical redundancy of the neovascularization process. In this scenario, multitarget compounds that are able to simultaneously tackle different proangiogenic pathways are eagerly awaited. UniPR1331 is a 3ß-hydroxy-Δ5-cholenic acid derivative, which is already known to inhibit Eph-ephrin interaction. Here, we employed an analysis pipeline consisting of molecular modeling and simulation, surface plasmon resonance spectrometry, biochemical assays, and endothelial cell models to demonstrate that UniPR1331 directly interacts with the vascular endothelial growth factor receptor 2 (VEGFR2) too. The binding of UniPR1331 to VEGFR2 prevents its interaction with the natural ligand vascular endothelial growth factor and subsequent autophosphorylation, signal transduction, and in vitro proangiogenic activation of endothelial cells. In vivo, UniPR1331 inhibits tumor cell-driven angiogenesis in zebrafish. Taken together, these data shed light on the pleiotropic pharmacological effect of UniPR1331, and point to Δ5-cholenic acid as a promising molecular scaffold for the development of multitarget antiangiogenic compounds.

3.
Pharmaceuticals (Basel) ; 14(6)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074058

RESUMO

Eph receptors, comprising A and B classes, interact with cell-bound ephrins generating bidirectional signaling. Although mainly related to carcinogenesis and organogenesis, the role of Eph/ephrin system in inflammation is growingly acknowledged. Recently, we showed that EphA/ephrin-A proteins can modulate the acute inflammatory responses induced by mesenteric ischemia/reperfusion, while beneficial effects were granted by EphB4, acting as EphB/ephrin-B antagonist, in a murine model of Crohn's disease (CD). Accordingly, we now aim to evaluate the effects of UniPR1331, a pan-Eph/ephrin antagonist, in TNBS-induced colitis and to ascertain whether UniPR1331 effects can be attributed to A- or B-type signaling interference. The potential anti-inflammatory action of UniPR1331 was compared to those of the recombinant proteins EphA2, a purported EphA/ephrin-A antagonist, and of ephrin-A1-Fc and EphA2-Fc, supposedly activating forward and reverse EphA/ephrin-A signaling, in murine TNBS-induced colitis and in stimulated cultured mononuclear splenocytes. UniPR1331 antagonized the inflammatory responses both in vivo, mimicking EphB4 protection, and in vitro; EphA/ephrin-A proteins were inactive or only weakly effective. Our findings represent a further proof-of-concept that blockade of EphB/ephrin-B signaling is a promising pharmacological strategy for CD management and highlight UniPR1331 as a novel drug candidate, seemingly working through the modulation of immune responses.

4.
Int J Mol Sci ; 22(5)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804570

RESUMO

Accumulating evidence indicates that an elevated ephrin-A1 expression is positively correlated with a worse prognosis in some cancers such as colon and liver cancer. The detailed mechanism of an elevated ephrin-A1 expression in a worse prognosis still remains to be fully elucidated. We previously reported that ADAM12-cleaved ephrin-A1 enhanced lung vascular permeability and thereby induced lung metastasis. However, it is still unclear whether or not cleaved forms of ephrin-A1 are derived from primary tumors and have biological activities. We identified the ADAM12-mediated cleavage site of ephrin-A1 by a Matrix-assisted laser desorption ionization mass spectrometry and checked levels of ephrin-A1 in the serum and the urine derived from the primary tumors by using a mouse model. We found elevated levels of tumor-derived ephrin-A1 in the serum and the urine in the tumor-bearing mice. Moreover, inhibition of ADAM-mediated cleavage of ephrin-A1 or antagonization of the EphA receptors resulted in a significant reduction of lung metastasis. The results suggest that tumor-derived ephrin-A1 is not only a potential biomarker to predict lung metastasis from the primary tumor highly expressing ephrin-A1 but also a therapeutic target of lung metastasis.


Assuntos
Proteína ADAM12/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Efrina-A1/metabolismo , Receptor EphA2/metabolismo , Proteína ADAM12/genética , Animais , Permeabilidade Capilar , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/metabolismo , Efrina-A1/genética , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Receptor EphA2/genética , Células Tumorais Cultivadas
5.
J Control Release ; 323: 412-420, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32325175

RESUMO

A novel pure insulin spray-dried powder for DPI product (Ins_SD) was studied with respect to physico-chemical stability, in vitro respirability, bioavailability, activity and tolerability. Ins_SD powder exhibited a very high in vitro respirability, independently of the DPI product preparation (manual or semi-automatic). Physico-chemical characteristics of Ins_SD powder remained within the pharmacopoeia limits during 6 months of storage at room temperature. PK/PD profiles were measured in rats that received the pulmonary powders by intratracheal insufflation and compared with Afrezza inhalation insulin. Due to the low drug powder mass to deliver, both insulin powders were diluted with mannitol. Insulin from Ins_SD was promptly absorbed (tmax 15 min and Cmaxx4.9 ±â€¯1.5 mU/ml). Afrezza had a slower absorption (tmax 30 min and Cmax of 1.8 ±â€¯0.37 mU/ml). After glucose injection, Ins_SD determined a rapid reduction of glucose level, similar to Afrezza. As reference, insulin subcutaneous injection showed a long-lasting hypoglycemic effect due to the slow absorption that prolonged insulin plasma level. In summary, Ins_SD product is suitable for post-prandial glucose control, providing a convenient and compliant product, in particular in the event of using a disposable device. Albeit the product has to be stored in fridge, its stability at room temperature allows the diabetic individual to carry the daily dose in normal conditions.


Assuntos
Excipientes , Insulina , Administração por Inalação , Animais , Inaladores de Pó Seco , Tamanho da Partícula , Pós , Ratos
6.
Pharmaceuticals (Basel) ; 13(4)2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32316101

RESUMO

The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development.

7.
Expert Opin Ther Targets ; 24(5): 403-415, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32197575

RESUMO

Introduction: The Eph-ephrin is a cell-cell communication system generating a forward signal in cell expressing Eph receptors and a reverse signal in ephrin-ligand expressing cells. While clearly involved in the insurgence and progression of cancer, the understanding of the molecular mechanisms regulated by this system needs development; this is a hurdle to the development of therapeutic strategies that can target the Eph receptors and/or their ephrin ligands.Areas covered: We have taken the opportunity to share some key questions on the most effective strategies to target the Eph-ephrin system. This article is based on our experience of the field and therefore is a Perspective and not comprehensive examination of the literature.Expert opinion: Targeting of the Eph-ephrin system has emerged as a potentially valuable approach for cancer therapy. Pharmacological tools have been reported in the last 15 years and these include forward signaling blockers such as kinases inhibitors and antagonists of forward and reverse signaling. Also, biologics including antibodies and recombinant proteins have been developed and some have reached early clinical stages. Data deem the Eph-ephrin system as a signaling axis that is an elusive target. A better understanding of the basic pharmacology behind the activity of available agents and a comprehensive knowledge of the ephrin biology are necessary. We are looking forward to knowing the opinion of the readers.


Assuntos
Efrinas/metabolismo , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Comunicação Celular/fisiologia , Progressão da Doença , Desenvolvimento de Medicamentos , Humanos , Ligantes , Neoplasias/patologia , Receptores da Família Eph/metabolismo
8.
J Pharm Biomed Anal ; 180: 113067, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31891876

RESUMO

The interest on the role of gut microbiota in the biotransformation of drugs and xenobiotics has grown over the last decades and a deeper understanding of the mutual interactions is expected to help future improvements in the fields of drug development, toxicological risk assessment and precision medicine. In this paper, a microbiome drug metabolism case is presented, involving a lipophilic small molecule, N-(3ß-hydroxy-Δ5-cholen-24-oyl)-l-tryptophan, UniPR1331, active as antagonist of the Eph-ephrin system and effective in vivo in a murine orthotopic model of glioblastoma multiforme (GBM). Following the administration of a single 30 mg/kg dose (p.o.) to mice, maximal plasma levels were reached 30 min after dosing and rapidly declined thereafter. To explain the observed in vivo behaviour, in vitro phase I and II metabolism assays were conducted employing mouse and human liver subcellular fractions and profiling main metabolites by means of tandem (HPLC-ESI-MS/MS) and high resolution mass spectrometry (HPLC-ESI-HR-MS). In the presence of in vitro mouse liver fractions, UniPR1331 showed a low phase I metabolic clearance, despite the identification of a 3-oxo and several hydroxylated metabolites. Conversely, after oral administration of UniPR1331 to mice, a novel isobaric metabolite was detected that (i) was subjected, as parent UniPR1331, to enterohepatic circulation (ii) had not been previously identified in vitro in mouse liver microsomes and (iii) was not observed forming after intraperitoneal (i.p.) administration of UniPR1331. An in vitro faecal fermentation assay produced the same chemical entity supporting a major role of gut microbiota in the in vivo clearance of UniPR1331.


Assuntos
Efrinas/antagonistas & inibidores , Microbioma Gastrointestinal/fisiologia , Microssomos Hepáticos/metabolismo , Receptores da Família Eph/antagonistas & inibidores , Animais , Bile/metabolismo , Cromatografia Líquida de Alta Pressão , Fezes/química , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Taxa de Depuração Metabólica , Desentoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
9.
Eur J Med Chem ; 189: 112083, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32000051

RESUMO

The EphA2 receptor has been validated in animal models as new target for treating tumors depending on angiogenesis and vasculogenic mimicry. In the present work, we extended our current knowledge on structure-activity relationship (SAR) data of two related classes of antagonists of the EphA2 receptor, namely 5ß-cholan-24-oic acids and 5ß-cholan-24-oyl l-ß-homotryptophan conjugates, with the aim to develop new antiangiogenic compounds able to efficiently prevent the formation of blood vessels. As a result of our exploration, we identified UniPR505, N-[3α-(Ethylcarbamoyl)oxy-5ß-cholan-24-oyl]-l-ß-homo-tryptophan (compound 14), as a submicromolar antagonist of the EphA2 receptor capable to block EphA2 phosphorylation and to inhibit neovascularization in a chorioallantoic membrane (CAM) assay.


Assuntos
Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/normas , Ácido Litocólico/química , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor EphA2/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Proliferação de Células , Embrião de Galinha , Galinhas , Membrana Corioalantoide , Humanos , Masculino , Modelos Moleculares , Fosforilação , Compostos Policíclicos/química , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/normas , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Life Sci ; 233: 116710, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369762

RESUMO

AIMS: The naturally occurring compound curcumin has been proposed for a number of pharmacological applications. In spite of the promising chemotherapeutic properties of the molecule, the use of curcumin has been largely limited by its chemical instability in water. In this work, we propose the use of water soluble proteins to overcome this issue in perspective applications to photodynamic therapy of tumors. MATERIALS AND METHODS: Curcumin was bound to bovine serum albumin and its photophysical properties was studied as well as its effect on cell viability after light exposure through MTT assay and confocal imaging. KEY FINDINGS: Bovine serum albumin binds curcumin with moderate affinity and solubilizes the hydrophobic compound preserving its photophysical properties for several hours. Cell viability assays demonstrate that when bound to serum albumin, curcumin is an effective photosensitizer for HeLa cells, with better performance than curcumin alone. Confocal fluorescence imaging reveals that when curcumin is delivered alone, it preferentially associates with mitochondria, whereas curcumin bound to bovine serum albumin is found in additional locations within the cell, a fact that may be related to the higher phototoxicity observed in this case. SIGNIFICANCE: The higher bioavailability of the photosensitizing compound curcumin when bound to serum albumin may be exploited to increase the efficiency of the drug in photodynamic therapy of tumors.


Assuntos
Apoproteínas/metabolismo , Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Sistemas de Liberação de Medicamentos , Mioglobina/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Soroalbumina Bovina/metabolismo , Animais , Apoproteínas/química , Apoptose/efeitos da radiação , Bovinos , Sobrevivência Celular , Curcumina/química , Células HeLa , Cavalos , Humanos , Mioglobina/química , Fármacos Fotossensibilizantes/química , Soroalbumina Bovina/química
11.
Front Pharmacol ; 10: 691, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31297055

RESUMO

Besides their long-known critical role in embryonic growth and in cancer development and progression, erythropoietin-producing hepatocellular carcinoma type B (EphB) receptor tyrosine kinases and their ephrin-B ligands are involved in the modulation of immune responses and in remodeling and maintaining the integrity of the intestinal epithelial layer. These processes are critically involved in the pathogenesis of inflammatory-based disorders of the gut, like inflammatory bowel diseases (IBDs). Accordingly, our aim was to investigate the role of the EphB/ephrin-B system in intestinal inflammation by assessing the local and systemic effects produced by its pharmacological manipulation in 2,4,6-trinitrobenzenesulfonic acid (TNBS)- (Th1-dependent model) and dextran sulphate sodium (DSS)- (innate response model) induced colitis in mice. To this purpose, we administered chimeric Fc-conjugated proteins, allegedly able to uni-directionally activate either forward (ephrin-B1-Fc) or reverse (EphB1-Fc) signaling, and the soluble monomeric EphB4 extracellular domain protein, that, simultaneously interfering with both signaling pathways, acts as EphB/ephrin-B antagonist.The blockade of the EphB/ephrin-B forward signaling by EphB4 and EphB1-Fc was ineffective against DSS-induced colitis while it evoked remarkable beneficial effects against TNBS colitis: it counteracted all the evaluated inflammatory responses and the changes elicited on splenic T lymphocytes subpopulations, without preventing the appearance of a splice variant of ephrin-B2 gene elicited by the haptenating agent in the colon. Interestingly, EphB4, preferentially displacing EphB4/ephrin-B2 interaction over EphB1/ephrin-B1 binding, was able to promote Tumor Necrosis Factor alpha (TNFα) release by splenic mononuclear cells in vitro. On the whole, the collected results point to a potential role of the EphB/ephrin-B system as a pharmacological target in intestinal inflammatory disorders and suggest that the therapeutic efficacy of its blockade seemingly works through the modulation of immune responses, independent of the changes at the transcriptional and translational level of EphB4 and ephrin-B2 genes.

12.
Biomacromolecules ; 20(5): 2024-2033, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30995399

RESUMO

Bioavailability of photosensitizers for cancer photodynamic therapy is often hampered by their low solubility in water. Here, we overcome this issue by using the water-soluble protein apomyoglobin (apoMb) as a carrier for the photosensitizer hypericin (Hyp). The Hyp-apoMb complex is quickly uptaken by HeLa and PC3 cells at submicromolar concentrations. Fluorescence emission of Hyp-apoMb is exploited to localize the cellular distribution of the photosensitizer. The plasma membrane is rapidly and efficiently loaded, and fluorescence is observed in the cytoplasm only at later times and to a lesser extent. Comparison with cells loaded with Hyp alone demonstrates that the uptake of the photosensitizer without the protein carrier is a slower, less efficient process, that involves the whole cell structure without preferential accumulation at the plasma membrane. Cell viability assays demonstrate that the Hyp-apoMb exhibits superior performance over Hyp. Similar results were obtained using tumor spheroids as three-dimensional cell culture models.


Assuntos
Antineoplásicos/administração & dosagem , Apoproteínas/química , Portadores de Fármacos/química , Mioglobina/química , Perileno/análogos & derivados , Fármacos Fotossensibilizantes/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Perileno/administração & dosagem , Perileno/química , Perileno/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Esferoides Celulares/efeitos dos fármacos
13.
Oncotarget ; 9(36): 24347-24363, 2018 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-29849945

RESUMO

Glioblastoma multiforme (GBM) is the most malignant brain tumor, showing high resistance to standard therapeutic approaches that combine surgery, radiotherapy, and chemotherapy. As opposed to healthy tissues, EphA2 has been found highly expressed in specimens of glioblastoma, and increased expression of EphA2 has been shown to correlate with poor survival rates. Accordingly, agents blocking Eph receptor activity could represent a new therapeutic approach. Herein, we demonstrate that UniPR1331, a pan Eph receptor antagonist, possesses significant in vivo anti-angiogenic and anti-vasculogenic properties which lead to a significant anti-tumor activity in xenograft and orthotopic models of GBM. UniPR1331 halved the final volume of tumors when tested in xenografts (p<0.01) and enhanced the disease-free survival of treated animals in the orthotopic models of GBM both by using U87MG cells (40 vs 24 days of control, p<0.05) or TPC8 cells (52 vs 16 days, p<0.01). Further, the association of UniPR1331 with the anti-VEGF antibody Bevacizumab significantly increased the efficacy of both monotherapies in all tested models. Overall, our data promote UniPR1331 as a novel tool for tackling GBM.

14.
Drug Discov Today ; 23(7): 1416-1425, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29857163

RESUMO

Mesenteric ischemia is a surgical emergency caused by a transient reduction in blood perfusion to the bowel. Despite accounting for only 0.1% of hospital admissions and 1-2% of gastrointestinal diseases, its elusive symptoms often lead to dramatically high morbidity and mortality rates. The complex cascade of inflammatory events and mediators triggered by mesenteric ischemia-reperfusion (I/R) accounts for the plethora of proposed pharmacological targets and for the current lack of an efficacious drug strategy for its management. It is hoped that a deeper understanding of its pathogenesis and the preclinical therapeutic strategies identified to date and described herein will improve the translation into the clinical setting of the pharmacological armamentarium against a life-threatening disorder that is currently mainly managed surgically.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Descoberta de Drogas/métodos , Isquemia Mesentérica/tratamento farmacológico , Oclusão Vascular Mesentérica/tratamento farmacológico , Probióticos , Traumatismo por Reperfusão/tratamento farmacológico , Circulação Esplâncnica/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Isquemia Mesentérica/mortalidade , Isquemia Mesentérica/patologia , Isquemia Mesentérica/fisiopatologia , Oclusão Vascular Mesentérica/mortalidade , Oclusão Vascular Mesentérica/patologia , Oclusão Vascular Mesentérica/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/mortalidade , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia
15.
Biochem Pharmacol ; 147: 21-29, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29129483

RESUMO

Eph/ephrin system is an emerging target for cancer therapy but the lack of potent, stable and orally bioavailable compounds is impairing the development of the field. Since 2009 our research group has been devoted to the discovery and development of small molecules targeting Eph/ephrin system and our research culminated with the synthesis of UniPR129, a potent but problematic Eph/ephrin antagonist. Herein, we describe the in vitro pharmacological properties of two derivatives (UniPR139 and UniPR502) stemmed from structure of UniPR129. These two compounds acted as competitive and reversible antagonists of all Eph receptors reducing both ephrin-A1 and -B1 binding to EphAs and EphBs receptors in the low micromolar range. The compounds acted as antagonists inhibiting ephrin-A1-dependent EphA2 activation and UniPR139 exerted an anti-angiogenic effect, inhibiting HUVEC tube formation in vitro and VEGF-induced vessel formation in the chick chorioallantoic membrane assay. Finally, the oral bioavailability of UniPR139 represents a step forward in the search of molecules targeting the Eph/ephrin system and offers a new pharmacological tool useful for future in vivo studies.


Assuntos
Sistemas de Liberação de Medicamentos , Efrinas/metabolismo , Ácido Litocólico/análogos & derivados , Triptofano/análogos & derivados , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Embrião de Galinha , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Ácido Litocólico/química , Ácido Litocólico/metabolismo , Ligação Proteica/fisiologia , Triptofano/química , Triptofano/metabolismo
16.
Eur J Med Chem ; 142: 152-162, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28780190

RESUMO

It is well established that the Eph/ephrin system plays a central role in the embryonic development, with minor implications in the physiology of the adult. However, it is overexpressed and deregulated in a variety of tumors, with a primary involvement in tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. Targeting the Eph/ephrin system with biologicals, including antibodies and recombinant proteins, reduces tumor growth in animal models of hematological malignancies, breast, prostate, colon, head and neck cancers and glioblastoma. Currently, some of these biopharmaceutical agents are under investigations in phase I or phase II clinical trials. Peptides and small molecules targeting protein-protein-interaction (PPI) are in the late preclinical phase where they are showing promising activity in models of glioblastoma, ovarian and lung cancer. The present review summarizes the most critical findings proposing the Eph/ephrin signaling system as a new target in molecularly targeted oncology.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Efrinas/metabolismo , Neoplasias/tratamento farmacológico , Receptores da Família Eph/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Descoberta de Drogas/métodos , Humanos , Modelos Moleculares , Terapia de Alvo Molecular/métodos , Neoplasias/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
17.
Shock ; 48(6): 681-689, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28472014

RESUMO

Mesenteric ischemia-reperfusion (I/R)-induced injury targets primarily endothelial and epithelial cells, leading to a cascade of inflammatory events, eventually culminating in life-threatening syndromes. Hitherto, the role of Eph, the largest family of tyrosine kinase receptors, and of their cell-bound ephrin ligands, whose interaction generates a bidirectional signaling, is still debated in I/R injury. The aim of the present work was therefore to investigate the effects produced by unidirectional activation of forward signaling (administration of chimeric protein ephrinA1-Fc), of reverse signaling (EphA2-Fc), or inhibition of both signals (monomeric EphA2 and the protein-protein interaction inhibitor UniPR1331) on the local and systemic inflammatory responses triggered by mesenteric I/R in mice.When administered at 200 µg/kg i.v., ephrin-A1-Fc prevented intestinal and lung I/R-induced injury, decreasing in the pulmonary district leukocytes recruitment, IL-1ß and TNFα levels, and EphA2 overexpression by mesenteric I/R. Blockade of Eph-ephrin signaling by equimolar EphA2 efficiently antagonized I/R-induced gut edema formation, an effect shared also by UniPR1331, mitigated lung mucosal injury, and counteracted the increase in pro-inflammatory cytokines levels. EphA2-Fc 180 µg/kg or equimolar Fc alone did not significantly modify the inflammatory responses to I/R.Our data suggest that the Eph-ephrin system is directly involved in the development of the acute inflammatory process activated in the gut by hypoxia-reoxygenation and in its amplification to distant organs, revealing that a fine pharmacological tuning of this signaling pathway may represent an attractive strategy to contain the I/R-induced inflammatory cascade.


Assuntos
Efrina-A1/farmacologia , Efrina-A2/metabolismo , Fragmentos Fc das Imunoglobulinas/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Traumatismo por Reperfusão , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Masculino , Mesentério/metabolismo , Mesentério/patologia , Camundongos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle
18.
J Med Chem ; 60(2): 787-796, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28005388

RESUMO

Metadynamics (META-D) is emerging as a powerful method for the computation of the multidimensional free-energy surface (FES) describing the protein-ligand binding process. Herein, the FES of unbinding of the antagonist N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan (UniPR129) from its EphA2 receptor was reconstructed by META-D simulations. The characterization of the free-energy minima identified on this FES proposes a binding mode fully consistent with previously reported and new structure-activity relationship data. To validate this binding mode, new N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan derivatives were designed, synthesized, and tested for their ability to displace ephrin-A1 from the EphA2 receptor. Among them, two antagonists, namely compounds 21 and 22, displayed high affinity versus the EphA2 receptor and resulted endowed with better physicochemical and pharmacokinetic properties than the parent compound. These findings highlight the importance of free-energy calculations in drug design, confirming that META-D simulations can be used to successfully design novel bioactive compounds.


Assuntos
Simulação por Computador , Desenho de Fármacos , Ácido Litocólico/análogos & derivados , Receptor EphA2/antagonistas & inibidores , Triptofano/análogos & derivados , Animais , Estabilidade de Medicamentos , Ligantes , Ácido Litocólico/administração & dosagem , Ácido Litocólico/síntese química , Ácido Litocólico/química , Ácido Litocólico/farmacocinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor EphA2/química , Relação Estrutura-Atividade , Triptofano/administração & dosagem , Triptofano/síntese química , Triptofano/química , Triptofano/farmacocinética
19.
Chemistry ; 22(24): 8048-52, 2016 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-27139720

RESUMO

The free-energy surface (FES) of protein-ligand binding contains information useful for drug design. Here we show how to exploit a free-energy minimum of a protein-ligand complex identified by metadynamics simulations to design a new EphA2 antagonist with improved inhibitory potency.


Assuntos
Desenho de Fármacos , Receptor EphA2/metabolismo , Sítios de Ligação , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptor EphA2/antagonistas & inibidores , Ressonância de Plasmônio de Superfície , Termodinâmica
20.
Biochem Pharmacol ; 99: 18-30, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26462575

RESUMO

Amino acid conjugates of lithocholic acid (LCA) have been recently described as effective disruptors of the EphA2-ephrin-A1 interaction able to inhibit EphA2 phosphorylation in intact cells and thus able to block prometastatic responses such as cellular retraction and angiogenesis. However, these LCA-based compounds were significantly more potent at disrupting the EphA2-ephrin-A1 interaction than at blocking phenotype responses in cells, which might reflect an unclear mechanism of action or a metabolic issue responsible for a reduction of the compound concentration at the cell's surface. Through the synthesis of new compounds and their examination by a combination of cell-based assays and real-time interaction analysis by surface plasmon resonance, we showed at molecular level that l-tryptophan conjugates of lithocholic acid disrupt EphA2-ephrin-A1 interaction by targeting the EphA 2 receptor and that the presence of a polar group in position 3 of steroid scaffold is a key factor to increase the effective concentration of the compounds in cancer cell lines.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Receptor EphA2/antagonistas & inibidores , Receptor EphA2/metabolismo , Ressonância de Plasmônio de Superfície/métodos , Linhagem Celular Tumoral , Fenômenos Químicos , Humanos , Ácido Litocólico/análogos & derivados , Ácido Litocólico/química , Ácido Litocólico/metabolismo , Ácido Litocólico/farmacologia , Simulação de Acoplamento Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Triptofano/análogos & derivados , Triptofano/química , Triptofano/metabolismo , Triptofano/farmacologia
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