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1.
Int J Mol Sci ; 23(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35887060

RESUMO

Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8H)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3D835Y) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein-ligand binding affinity by employing molecular mechanics Poisson-Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure-activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC50 values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods.


Assuntos
Pteridinas , Tirosina Quinase 3 Semelhante a fms , Sítios de Ligação , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Tirosina Quinase 3 Semelhante a fms/genética
2.
Antiviral Res ; 205: 105384, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35863499

RESUMO

Foot-and-mouth disease (FMD) is an acute contagious disease of cloven-hoofed animals such as cows, pigs, sheep, and deer. The current emergency FMD vaccines, to induce early protection, have limited use, as their protective effect in pigs does not begin until 7 days after vaccination. Therefore, the use of antiviral agents would be required for reducing the spread of foot-and-mouth disease virus (FMDV) during outbreaks. Vesatolimod (GS-9620), a toll-like receptor 7 agonist, is an antiviral agent against various human disease-causing viruses. However, its antiviral effect against FMDV has not been reported yet. The aim of this study was to investigate the antiviral effects of GS-9620 against FMDV both in vitro and in vivo. The inhibitory effect of GS-9620 on FMDV in swine cells involved the induction of porcine interferon (IFN)-α and upregulation of interferon-simulated genes. Protective effect in mice injected with GS-9620 against FMDV was maintained for 5 days after injection, and cytokines such as IFN-γ, interleukin (IL)-12, IL-6, and IFN-γ inducible protein-10 could be detected following the treatment with GS-9620. Furthermore, the combination of GS-9620 with an FMD-inactivated vaccine was found to be highly effective for early protection in mice. Overall, we suggest GS-9620 as a novel and effective antiviral agent for controlling FMDV infection.


Assuntos
Cervos , Vírus da Febre Aftosa , Febre Aftosa , Vacinas Virais , Animais , Antivirais/uso terapêutico , Bovinos , Febre Aftosa/tratamento farmacológico , Febre Aftosa/prevenção & controle , Humanos , Interferon-alfa/farmacologia , Camundongos , Pteridinas , Ovinos , Suínos
3.
In Vivo ; 36(4): 1790-1794, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35738626

RESUMO

BACKGROUND/AIM: Indoxyl sulfate is a metabolite of tryptophan and its urinary level reflects the status of bacterial flora in the intestine. Indoxyl sulfate possesses prooxidant properties and is implicated in various diseases including chronic kidney disease and cardiovascular diseases. However, the relation of urinary indoxyl sulfate to oxidative stress is not known. PATIENTS AND METHODS: The association of urinary indoxyl sulfate levels with urinary levels of oxidative stress markers, 15-isoprostane F2t and pteridine derivatives, was investigated in 255 patients with type 2 diabetes. Indoxyl sulfate and pteridine derivatives were measured by using spectrofluorometry. RESULTS: Urinary levels of indoxyl sulfate, pteridines, and 15-isoprostane F2t showed a normal distribution after logarithmic transformation but not before it, and they were thus used for parametric analysis after logarithmic transformation. Urinary indoxyl sulfate levels were significantly correlated (p<0.01) with urinary 15-isoprostane F2t and pteridine levels [Pearson's correlation coefficients: 0.503 (15-isoprostane F2t) and 0.562 (pteridines)]. These associations were also found in multivariable analysis after adjusting for age, sex, insulin therapy for diabetes, body mass index, mean arterial pressure, hemoglobin A1c, estimated glomerular filtration rate, urinary albumin, and histories of smoking and alcohol drinking. CONCLUSION: Urinary indoxyl sulfate levels showed associations with urinary levels of oxidative stress markers, and the associations were independent of age, sex, insulin therapy for diabetes, body mass index, blood pressure, glycemic status, renal function, smoking, and alcohol drinking. Indoxyl sulfate appears to be an important determinant of redox balance in patients with diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Insulinas , Biomarcadores/metabolismo , Humanos , Indicã/metabolismo , Insulinas/metabolismo , Isoprostanos , Estresse Oxidativo/fisiologia , Pteridinas
4.
J Med Chem ; 65(13): 9011-9033, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35675511

RESUMO

The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.


Assuntos
Leishmania major , Oxirredutases , Tetra-Hidrofolato Desidrogenase , Trypanosoma brucei brucei , Leishmania major/efeitos dos fármacos , Leishmania major/enzimologia , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Pteridinas/química , Pteridinas/farmacologia , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/enzimologia
5.
J Photochem Photobiol B ; 232: 112477, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35644070

RESUMO

In the present work, the interactions of the novel kinase inhibitors BI-2536, Volasetib (BI-6727) and Ro-3280 with the pharmacological target PLK1 have been studied by fluorescence spectroscopy and molecular dynamics calculations. High Stern-Volmer constants were found in fluorescence experiments suggesting the formation of stable protein-ligand complexes. In addition, it was observed that the binding constant between BI-2536 and PLK1 increases about 100-fold in presence of the phosphopeptide Cdc25C-p that docks to the polo box domain of the protein and releases the kinase domain. All the determined binding constants are higher for the kinase inhibitors than for their competitor for the active center (ATP) being BI-2536 and Volasertib the inhibitors that showed more affinity for PLK1. Calculated binding free energies confirmed the higher affinity of PLK1 for BI-2536 and Volasertib than for ATP. The higher affinity of the inhibitors to PLK1 compared to ATP was mainly attributed to stronger van der Waals interactions. Results may help with the challenge of designing and developing new kinase inhibitors more effective in clinical cancer therapy.


Assuntos
Proteínas de Ciclo Celular , Trifosfato de Adenosina , Proteínas de Ciclo Celular/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas
6.
BMC Cancer ; 22(1): 569, 2022 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-35597904

RESUMO

BACKGROUND: This report summarizes three phase I studies evaluating volasertib, a polo-like kinase inhibitor, plus azacitidine in adults with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia. METHODS: Patients received intravenous volasertib in 28-day cycles (dose-escalation schedules). In Part 1 of 1230.33 (Study 1; NCT01957644), patients received 250-350 mg volasertib on day (D)1 and D15; in Part 2, patients received different schedules [A, D1: 170 mg/m2; B, D7: 170 mg/m2; C, D1 and D7: 110 mg/m2]. In 1230.35 (Study 2; NCT02201329), patients received 200-300 mg volasertib on D1 and D15. In 1230.43 (Study 3; NCT02721875), patients received 110 mg/m2 volasertib on D1 and D8. All patients in Studies 1 and 2, and approximately half of the patients in Study 3, were scheduled to receive subcutaneous azacitidine 75 mg/m2 on D1-7. RESULTS: Overall, 22 patients were treated (17 with MDS; 12 previously untreated). Across Studies 1 and 2 (n = 21), the most common drug-related adverse events were hematological (thrombocytopenia [n = 11]; neutropenia [n = 8]). All dose-limiting toxicities were grade 4 thrombocytopenia. The only treated patient in Study 3 experienced 18 adverse events following volasertib monotherapy. Studies 1 and 2 showed preliminary activity (objective response rates: 25 and 40%). CONCLUSIONS: The safety of volasertib with azacitidine in patients with MDS was consistent with other volasertib studies. All studies were terminated prematurely following the discontinuation of volasertib for non-clinical reasons by Boehringer Ingelheim; however, safety information on volasertib plus azacitidine are of interest for future studies in other diseases.


Assuntos
Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Trombocitopenia , Adulto , Azacitidina/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mielomonocítica Crônica/induzido quimicamente , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/tratamento farmacológico , Pteridinas , Trombocitopenia/induzido quimicamente
7.
Metabolomics ; 18(5): 27, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35482254

RESUMO

INTRODUCTION: Determining the biological significance of pteridines in cancer development and progression remains an important step in understanding the altered levels of urinary pteridines seen in certain cancers. Our companion study revealed that several folate-derived pteridines and lumazines correlated with tumorigenicity in an isogenic, progressive breast cancer cell model, providing direct evidence for the tumorigenic origin of pteridines. OBJECTIVES: This study sought to elucidate the pteridine biosynthetic pathway in a progressive breast cancer model via direct pteridine dosing to determine how pteridine metabolism changes with tumorigenicity. METHODS: First, MCF10AT breast cancer cells were dosed individually with 15 pteridines to determine which pteridines were being metabolized and what metabolic products were being produced. Second, pteridines that were significantly metabolized were dosed individually across the progressive breast cancer cell model (MCF10A, MCF10AT, and MCF10ACA1a) to determine the relationship between each metabolic reaction and breast cancer tumorigenicity. RESULTS: Several pteridines were found to have altered metabolism in breast cancer cell lines, including pterin, isoxanthopterin, xanthopterin, sepiapterin, 6-biopterin, lumazine, and 7-hydroxylumazine (p < 0.05). In particular, isoxanthopterin and 6-biopterin concentrations were differentially expressed (p < 0.05) with respect to tumorigenicity following dosing with pterin and sepiapterin, respectively. Finally, the pteridine biosynthetic pathway in breast cancer cells was proposed based on these findings. CONCLUSIONS: This study, along with its companion study, demonstrates that pteridine metabolism becomes disrupted in breast cancer tumor cells. This work highlights several key metabolic reactions within the pteridine biosynthetic pathway that may be targeted for further investigation and clinical applications.


Assuntos
Neoplasias da Mama , Biopterina , Neoplasias da Mama/urina , Feminino , Humanos , Metabolômica , Pteridinas/metabolismo , Pterinas
8.
J Inorg Biochem ; 231: 111801, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35339771

RESUMO

Over 50 molybdenum enzymes in three distinct families (sulfite oxidase, xanthine oxidase, DMSO reductase) are known, and representative X-ray crystal structures are available for all families. Structural analogues that replicate the coordination about the Mo atom in the absence of surrounding protein have been synthesized and characterized. The properties of metal complexes of non-innocent dithiolene ligands and their oxidized counter parts, dithiones, are summarized. Pulsed electron paramagnetic resonance (EPR) spectroscopy of the 33S-labeled molybdenum domain of catalytically active bioengineered sulfite oxidase has clearly demonstrated delocalization of electron density from MoV to the dithiolene component of the molybdenum cofactor (Moco) of the enzyme. Moco is highly covalent and has three redox active components: the Mo atom; the dithiolene; and the pterin. In principle, Moco can have a total of eight redox states, making it one of the most redox rich cofactors in biology. The {Moco}n formalism, developed here, gives the total number of electrons (n) associated with a particular redox state of Moco. This flexible notation eliminates the need to assign a specific oxidation state to each of the three components of Moco and allows for internal redistribution of electrons among the components upon substrate binding, changes in the surrounding network of hydrogen bonds, conformational changes, and catalysis. An unexpected result is that sulfite oxidase (an oxotransferase) is predicted to utilize the {Moco}4-6 electron distributions during catalysis, whereas xanthine oxidase (a hydroxylase) is predicted to utilize the {Moco}6-8 electron distributions during catalysis.


Assuntos
Metaloproteínas , Sulfito Oxidase , Coenzimas/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Molibdênio/química , Pteridinas , Sulfito Oxidase/química
9.
J Inherit Metab Dis ; 45(3): 456-469, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35192225

RESUMO

Molybdenum cofactor deficiency (MoCD) includes three ultrarare autosomal recessive inborn errors of metabolism (MoCD type A [MoCD-A], MoCD-B, and MoCD-C) that cause sulfite intoxication disorders. This natural history study analyzed retrospective data for 58 living or deceased patients (MoCD-A, n = 41; MoCD-B, n = 17). MoCD genotype, survival, neuroimaging, and medical history were assessed retrospectively. Prospective biomarker data were collected for 21 living MoCD patients. The primary endpoint was survival to 1 year of age in MoCD-A patients. Of the 58 MoCD patients, 49 (MoCD-A, n = 36; MoCD-B, n = 13) had first presenting symptoms by Day 28 (neonatal onset; median: 2 and 4 days, respectively). One-year survival rates were 77.4% (overall), 71.8% (neonatal onset MoCD-A), and 76.9% (neonatal onset MoCD-B); median ages at death were 2.4, 2.4, and 2.2 years, respectively. The most common presenting symptoms in the overall population were seizures (60.3%) and feeding difficulties (53.4%). Sequelae included profound developmental delay, truncal hypotonia, limb hypertonia that evolved to spastic quadriplegia or diplegia, dysmorphic features, and acquired microcephaly. In MoCD-A and MoCD-B, plasma and urinary xanthine and S-sulfocysteine concentrations were high; urate remained below the normal reference range. MOCS1 mutation homozygosity was common. Six novel mutations were identified. MoCD is a severe neurodegenerative disorder that often manifests during the neonatal period with intractable seizures and feeding difficulties, with rapidly progressive significant neurologic disabilities and high 1-year mortality rates. Delineation of MoCD natural history supports evaluations of emerging replacement therapy with cPMP for MoCD-A, which may modify disease course for affected individuals.


Assuntos
Erros Inatos do Metabolismo dos Metais , Metaloproteínas , Coenzimas , Humanos , Recém-Nascido , Erros Inatos do Metabolismo dos Metais/diagnóstico , Estudos Prospectivos , Pteridinas , Estudos Retrospectivos , Convulsões/complicações
10.
Comput Math Methods Med ; 2022: 2032895, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186110

RESUMO

BACKGROUND: A majority of relapse cases have been reported in colorectal cancer patients due to cancer stem cell progenitors. The factors responsible for chemoresistance have yet to be discovered and investigated as CSCs have reported escaping from chemotherapy's killing action. OBJECTIVE: In this study, we have investigated the effects of HIF-1α and TGF-ß2 in hypoxia conditions on the expression of GLI2, which is a potential factor for causing chemoresistance. Material and Methods. Colorectal samples of treated patients were collected from the Hospital Biological Sample Library. Culture of patient-derived TSs and fibroblasts was performed. The collected patient samples and cells were used for immunohistochemistry, quantitative PCR, and western blotting studies which were performed. RESULTS: It was reported that HIF-1α (hypoxia-inducible factor) and TGF-ß2 secreted from cancer-associated fibroblasts (CAFs) synergistically work to express GLI2 in cancer stem cells. Hence, it increased the stemness as well as resistance to chemotherapy. CONCLUSION: The HIF-1α/TGF-ß2-mediated GLI2 signaling was responsible for causing chemoresistance in the hypoxia environment. High expressions of HIF1α/TGF-ß2/GLI2 cause the relapsing of colorectal cancer, thus making this a potential biomarker for identifying the relapse and resistance in patients. The study uncovers the mechanism involved in sternness and chemotherapy resistance which will help in targeted treatment.


Assuntos
Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Nucleares/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Proteína Gli2 com Dedos de Zinco/metabolismo , Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Biologia Computacional , Resistencia a Medicamentos Antineoplásicos , Humanos , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Pteridinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Células Tumorais Cultivadas , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Proteína Gli2 com Dedos de Zinco/antagonistas & inibidores
11.
J Med Chem ; 65(3): 2694-2709, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35099969

RESUMO

Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK inhibitors have been developed, among which covalent BTK inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of ITK and EGFR. In this study, we disclosed a series of pteridine-7(8H)-one derivatives as potent and selective covalent BTK inhibitors, which were optimized from 3z, an EGFR inhibitor previously reported by our group. Among them, compound 24a exhibited great BTK inhibition activity (IC50 = 4.0 nM) and high selectivity in both enzymatic (ITK >250-fold, EGFR >2500-fold) and cellular levels (ITK >227-fold, EGFR 27-fold). In U-937 xenograft models, 24a significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, 24a is a new BTK inhibitor worthy of further development.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pteridinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Pteridinas/síntese química , Pteridinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Sci ; 113(1): 132-144, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34668620

RESUMO

In solid tumors, cancer cells have devised multiple approaches to survival and proliferate in response to glucose starvation that is often observed in solid tumor microenvironments. However, the precise mechanisms are far less known. Herein, we report that glucose deprivation activates 90-kDa ribosomal S6 kinase (p90 RSK), a highly conserved Ser/Thr kinase, and activated p90 RSK promotes cancer cell survival. Mechanistically, activated p90 RSK by glucose deprivation phosphorylates checkpoint kinase 1 (CHK1), a key transducer in checkpoint signaling pathways, at Ser280 and triggers CHK1 ubiquitination mediated by SCFß-TrCP ubiquitin ligase and proteasomal degradation, subsequently suppressing cancer cell apoptosis induced by glucose deprivation. Importantly, we identified an inverse correlation between p90 RSK activity and CHK1 levels within the solid tumor mass, with lower levels of CHK1 and higher activity of p90 RSK in the center of the tumor where low glucose concentrations are often observed. Thus, our study indicates that p90 RSK promotes CHK1 phosphorylation at Ser280 and its subsequent degradation, which allows cancer cells to escape from checkpoint signals under the stress of glucose deprivation, leading to cell survival and thus contributing to tumorigenesis.


Assuntos
Quinase 1 do Ponto de Checagem/metabolismo , Glucose/deficiência , Neoplasias/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Quinase 1 do Ponto de Checagem/química , Ativação Enzimática , Células HEK293 , Humanos , Camundongos , Fosforilação , Proteólise/efeitos dos fármacos , Pteridinas/farmacologia , Ubiquitinação/efeitos dos fármacos
13.
Med Chem ; 18(3): 353-363, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34097593

RESUMO

BACKGROUND: Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR which are attractive targets for the anticancer therapy. OBJECTIVE: This work aimed at designing and synthesizing 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor. METHODS: Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17]. RESULTS: The compound 7m, with IC50 values of 27.40 µM on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides, western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 µM. The molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lied at the ATP binding site of EGFR kinase domain. CONCLUSION: The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the antiproliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for the modification of pteridine-based derivatives as EGFR inhibitor.


Assuntos
Antineoplásicos , Pteridinas , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pteridinas/farmacologia , Relação Estrutura-Atividade
14.
Metabolomics ; 18(1): 2, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34919200

RESUMO

INTRODUCTION: Pteridines include folate-derived metabolites that have been putatively associated with certain cancers in clinical studies. However, their biological significance in cancer metabolism and role in cancer development and progression remains poorly understood. OBJECTIVES: The purpose of this study was to examine the effects of tumorigenicity on pteridine metabolism by studying a panel of 15 pteridine derivatives using a progressive breast cancer cell line model with and without folic acid dosing. METHODS: The MCF10A progressive breast cancer model, including sequentially derived MCF10A (benign), MCF10AT (premalignant), and MCF10CA1a (malignant) cell lines were dosed with 0, 100, and 250 mg/L folic acid. Pteridines were analyzed in both intracellular and extracellular contexts using an improved high-performance liquid chromatography-tandem mass spectrometry method. RESULTS: Pteridines were located predominately in the extracellular media. Folic acid dosing increased extracellular levels of pterin, 6-hydroxylumazine, xanthopterin, 6-hydroxymethylpterin, and 6-carboxypterin in a dose-dependent manner. In particular, pterin and 6-hydroxylumazine levels were positively correlated with tumorigenicity upon folate dosing. CONCLUSIONS: Folic acid is a primary driver for pteridine metabolism in human breast cell. Higher folate levels contribute to increased formation and excretion of pteridine derivatives to the extracellular media. In breast cancer, this metabolic pathway becomes dysregulated, resulting in the excretion of certain pteridine derivatives and providing in vitro evidence for the observation of elevated pteridines in the urine of breast cancer patients. Finally, this study reports a novel use of the MCF10A progressive breast cancer model for metabolomics applications that may readily be applied to other metabolites of interest.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/patologia , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Metabolômica , Pteridinas/urina
15.
Bull Cancer ; 108(9S1): S22-S32, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34955159

RESUMO

The panel of therapeutic options available for medical treatment of relapsed ovarian cancer increased over the last years. In late, platinum-sensitive relapse, standard treatment remains platinum-based polychemotherapy. The choice between bevacizumab added to chemotherapy followed by maintenance and inhibitors of poly-(ADP-riboses) polymerases (PARPi) after response to platinum-based therapy should be discussed, taking into account prior treatment, contraindications, and disease characteristics (biology, symptoms…). The addition of bevacizumab at first platinum-sensitive relapse can be considered if it has not been administered in first line, and it is optional (rechallenge) if previously administered (but without Marketing Authorization in this setting). PARPi are indicated for maintenance therapy after response to platinum-based chemotherapy (whatever the treatment line), regardless of BRCA mutational status, in case of no prior administration. Early relapses are associated with poor prognosis and therapeutic options are more limited. They are treated by monochemotherapy without platinum agents, associated with bevacizumab if not administered previously. Beyond first early relapse, there is no standard and inclusion in a clinical trial should be proposed if possible. Several clinical studies assessing associations of immunotherapy and chemotherapy and/or antiangiogenic drugs and/or targeted therapies (such as PARPi) are ongoing in early or late relapse.


Assuntos
Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azepinas/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Epitelial do Ovário/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia , Isoxazóis/uso terapêutico , Quimioterapia de Manutenção/métodos , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Recidiva Local de Neoplasia/genética , Compostos de Platina/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Pteridinas/uso terapêutico , Pirazinas/uso terapêutico , Pirimidinas/uso terapêutico
16.
SAR QSAR Environ Res ; 32(12): 985-1011, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34845959

RESUMO

The origin of cancer is related to the dysregulation of multiple signal pathways and of physiological processes. Bromodomain-containing protein 4 (BRD4) has become an attractive target for the development of anticancer and anti-inflammatory agents since it can epigenetically regulate the transcription of growth-promoting genes. The synthesized BRD4 inhibitors with new chemical structures can reduce the drug resistance, but their binding modes and the inhibitory mechanism remain unclear. Here, we initially constructed robust QSAR models based on 68 reported tetrahydropteridin analogues using topomer CoMFA and HQSAR. On the basis of QSAR results, we designed 16 novel tetrahydropteridin analogues with modified structures and carried out docking studies. Instead of significant hydrogen bondings with amino acid residue Asn140 as reported in previous research, the molecular docking modelling suggested a novel docking pose that involves the amino acid residues (Trp81, Pro82, Val87, Leu92, Leu94, Cys136, Asp144, and Ile146) at the active site of BRD4. The MD simulations, free energy calculations, and residual energy contributions all indicate that hydrophobic interactions are decisive factors affecting bindings between inhibitors and BRD4. The current study provides new insights that can aid the discovery of BRD4 inhibitors with enhanced anti-cancer ability.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Pteridinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pteridinas/química , Fatores de Transcrição/química
17.
Biol Pharm Bull ; 44(12): 1843-1850, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34602526

RESUMO

Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations drive malignancy in acute myeloid leukemia (AML), which accounts for approximately 40% of AML cases. Treatment with FLT3 or IDH1/2 inhibitors is used for such patients; however, it is not considered for most patients with AML who lack mutations on the respective genes. In this study, p90 ribosomal S6 kinase (RSK) was found to serve as a new therapeutic target in various AMLs with or without FLT3 mutations. BI-D1870, a potent inhibitor of RSK, significantly suppressed the proliferation of AML cell lines, among which three encoded wild-type FLT3 and three contained FLT3 driver mutations, compared with chronic myeloid leukemia K562 cells or other adherent cancer cells. BI-D1870 inhibited protein synthesis by dephosphorylating the p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in all AML cells except KG-1a cells. Meanwhile, the expression of microtubule-associated protein light chain 3B-I and -II increased in KG-1a cells treated with BI-D1870. BI-D1870 induced caspase-dependent apoptosis in all AML cells, including KG-1a cells. We next investigated the synergistic effect of BI-D1870 with cytarabine, a traditional anticancer drug used in AML. Synergistic effects of BI-D1870 and cytarabine were not observed in any of the cell lines. The findings suggested that BI-D1870 alone exerts an adequate antiproliferative effect on AML with or without FLT3 mutations and serves as a novel AML therapeutic agent.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Fatores de Iniciação em Eucariotos/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Pteridinas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética
18.
Biomed Pharmacother ; 144: 112347, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34700228

RESUMO

New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients' outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29R, RKOR, SW837R and HCT116R, were generated in vitro and validated by IG50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKOR. AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29R, SW837R and HCT116R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Ácido Mevalônico/metabolismo , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Sinvastatina/farmacologia , Proteína 1 Relacionada a Twist/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Células HCT116 , Células HT29 , Humanos , Camundongos Nus , Mutação , Proteínas Nucleares/genética , /metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais , Proteína 1 Relacionada a Twist/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Front Immunol ; 12: 745802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671360

RESUMO

Immune modulation for the treatment of chronic hepatitis B (CHB) has gained more traction in recent years, with an increasing number of compounds designed for targeting different host pattern recognition receptors (PRRs). These agonistic molecules activate the receptor signaling pathway and trigger an innate immune response that will eventually shape the adaptive immunity for control of chronic infection with hepatitis B virus (HBV). While definitive recognition of HBV nucleic acids by PRRs during viral infection still needs to be elucidated, several viral RNA sensing receptors, including toll-like receptors 7/8/9 and retinoic acid inducible gene-I-like receptors, are explored preclinically and clinically as possible anti-HBV targets. The antiviral potential of viral DNA sensing receptors is less investigated. In the present study, treatment of primary woodchuck hepatocytes generated from animals with CHB with HSV-60 or poly(dA:dT) agonists resulted in increased expression of interferon-gamma inducible protein 16 (IFI16) or Z-DNA-binding protein 1 (ZBP1/DAI) and absent in melanoma 2 (AIM2) receptors and their respective adaptor molecules and effector cytokines. Cytosolic DNA sensing receptor pathway activation correlated with a decline in woodchuck hepatitis virus (WHV) replication and secretion in these cells. Combination treatment with HSV-60 and poly(dA:dT) achieved a superior antiviral effect over monotreatment with either agonist that was associated with an increased expression of effector cytokines. The antiviral effect, however, could not be enhanced further by providing additional type-I interferons (IFNs) exogenously, indicating a saturated level of effector cytokines produced by these receptors following agonism. In WHV-uninfected woodchucks, a single poly(dA:dT) dose administered via liver-targeted delivery was well-tolerated and induced the intrahepatic expression of ZBP1/DAI and AIM2 receptors and their effector cytokines, IFN-ß and interleukins 1ß and 18. Receptor agonism also resulted in increased IFN-γ secretion of peripheral blood cells. Altogether, the effect on WHV replication and secretion following in vitro activation of IFI16, ZBP1/DAI, and AIM2 receptor pathways suggested an antiviral benefit of targeting more than one cytosolic DNA receptor. In addition, the in vivo activation of ZBP1/DAI and AIM2 receptor pathways in liver indicated the feasibility of the agonist delivery approach for future evaluation of therapeutic efficacy against HBV in woodchucks with CHB.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B da Marmota/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Poli dA-dT/farmacologia , Receptores de Superfície Celular/agonistas , Receptores de Reconhecimento de Padrão/agonistas , Receptores Virais/agonistas , Animais , Antivirais/uso terapêutico , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Citosol/virologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Hepatite B/imunologia , Hepatite B/virologia , Vírus da Hepatite B da Marmota/fisiologia , Hepatócitos/virologia , Imunidade Inata , Interferons/farmacologia , Fígado/efeitos dos fármacos , Fígado/virologia , Marmota , Poli dA-dT/uso terapêutico , Pteridinas/farmacologia , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Receptores de Reconhecimento de Padrão/biossíntese , Receptores de Reconhecimento de Padrão/genética , Receptores Virais/biossíntese , Receptores Virais/genética , Replicação Viral/efeitos dos fármacos
20.
Bioorg Chem ; 116: 105324, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34509794

RESUMO

CDK4/6 have been validated as the cancer therapeutic targets. Here, we describe a series of pteridin-7(8H)-one analogues as potent CDK4/6 inhibitors. Among them, the most promising compound 7s demonstrated remarkable and broad-spectrum antiproliferative activities toward HCT116, HeLa, MDA-MB-231, and HT-29 cells with IC50 values of 0.65, 0.70, 0.39, and 2.53 µM, respectively, which were more potent than that of the anticancer drug Palbociclib. Interestingly, 7s also manifested the greatest inhibitory activities toward both CDK4/cyclin D3 and CDK6/cyclin D3 (IC50 = 34.0 and 65.1 nM, respectively), which was comparable with Palbociclib. Additionally, molecular simulation indicated that 7s bound efficiently at the ATPbindingsitesofCDK4 and CDK6. Further mechanistic studies revealed that compound 7s could concentration-dependently induce cell cycle arrest and apoptosis in HeLa cells. Takentogether, 7s represents a promising novel CDK4/6 inhibitor for the potential treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Desenvolvimento de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pteridinas/síntese química , Pteridinas/química , Relação Estrutura-Atividade
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