Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Cancer Ther ; 22(1): 12-24, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36279567

RESUMO

Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with antimitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-851, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemoresistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, cotreatment of ER-851 and antimitotic drugs produced an antitumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-851 is a promising candidate therapeutic agent for use against AXL-expressing antimitotic-resistant tumors.


Assuntos
Antimitóticos , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Receptor Tirosina Quinase Axl , Antimitóticos/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem Lett ; 48: 128247, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34271070

RESUMO

Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , c-Mer Tirosina Quinase/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , c-Mer Tirosina Quinase/metabolismo , Receptor Tirosina Quinase Axl
3.
Bioorg Med Chem ; 39: 116137, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33930844

RESUMO

Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Camundongos , Modelos Animais , Inibidores de Proteínas Quinases/química , Retina/efeitos dos fármacos , Análise Espectral/métodos , Relação Estrutura-Atividade , Receptor Tirosina Quinase Axl
4.
Toxicology ; 411: 163-171, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30336191

RESUMO

Circulating miR-96-5p, -124-3p, and 183-5p have been reported as safety biomarkers for retinal toxicity. In the present research, 5 serum microRNAs (miRNAs), which are highly specific to and abundant in the retina, including the 3 miRNAs previously mentioned, were assessed in 3 different models of retinal toxicity. Distinct types of retinal lesions were induced in rats by a single dose of N-methyl-N-nitrosourea (MNU: 10, 30, and 50 mg/kg, i.p.), N-methyl-d-aspartate (NMDA: 200 nmol/eye, intravitreal injection), or sodium iodate (NaIO3: 30 mg/kg, i.v.). Time-course change of serum miRNAs was evaluated by RT-PCR for up to 1 week after administration. Ophthalmologic and histologic examinations and electroretinogram recording were also performed. MNU at 50 mg/kg induced photoreceptor cell death, with elevation in serum miR-96-5p, -124-3p, and -183-5p levels. NMDA induced retinal ganglion and inner nuclear layer cell death, with elevation in serum miR-124-3p. In both models, serum miRNA elevations occurred in parallel with the onset of neuroretinal cell death and retinal dysfunction. NaIO3 induced retinal pigment epithelial cell death without changes in neuroretinal cell or serum miRNAs. In the present research, circulating miR-124-3p was elevated in a case of retinal ganglion and inner nuclear layer cell death as well as photoreceptor cell death. Our data suggest that different patterns of circulating miRNA elevations correspond to death of a specific neuroretinal cell. A miRNA panel consisting of miR-96-5p, -124-3p, and -183-5p may be used as a biomarker to detect neuroretinal cell death and identify the specific target cell.


Assuntos
Biomarcadores/sangue , MicroRNA Circulante/sangue , Doenças Retinianas/sangue , Doenças Retinianas/induzido quimicamente , Animais , Morte Celular/efeitos dos fármacos , Eletrorretinografia , Olho/patologia , Feminino , Iodatos/toxicidade , Masculino , Metilnitrosoureia/toxicidade , Mutagênicos/toxicidade , N-Metilaspartato/toxicidade , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Células Ganglionares da Retina/efeitos dos fármacos
5.
Reprod Toxicol ; 79: 89-95, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29928988

RESUMO

Farletuzumab is a humanized monoclonal antibody targeting human folate receptor alpha, which is being developed as an anti-cancer drug. A non-human primate reproductive study was conducted to evaluate whether it could cause any embryonic or fetal abnormalities. Farletuzumab was administered intravenously to pregnant cynomolgus monkeys (n = 16/group) at doses of 0 or 67.5 mg/kg once weekly during gestation day (GD) 20 through 97. C-section was performed on GD100 ±â€¯2, and fetuses were evaluated for morphologic (external, visceral and skeletal) effects. No farletuzumab-related changes were observed in maternal animals or fetuses, which are supported by the fact that farletuzumab has no effects on cellular uptake of folate. These data support the potential use of farletuzumab for oncologic indications during pregnancy.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Receptor 1 de Folato/antagonistas & inibidores , Animais , Anticorpos/sangue , Anticorpos Monoclonais Humanizados/sangue , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Feminino , Receptor 1 de Folato/metabolismo , Macaca fascicularis , Masculino , Troca Materno-Fetal , Gravidez
6.
J Toxicol Pathol ; 29(1): 31-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26989299

RESUMO

Plasmodium spp. protozoa cause malaria and are known to infect humans and a variety of animal species including macaque monkeys. Here we report both our experience with malaria recrudescence in cynomolgus monkeys (Macaca fascicularis) in a toxicity study and the results of a survey on Plasmodium infection in cynomolgus monkeys imported to Japan for laboratory use. A cynomolgus monkey from the toxicity study presented with severe anemia and Plasmodium protozoa in erythrocytes on a thin blood smear and was subsequently diagnosed with symptomatic malaria. In this animal, congestion and accumulation of hemozoin (malaria pigment) in macrophages were noted in the enlarged and darkly discolored spleen. As a follow-up for the experience, spleen sections from 800 cynomolgus monkeys in toxicity studies conducted between 2003 and 2013 were retrospectively examined for hemozoin deposition as a marker of Plasmodium infection. The origin of the animals included Cambodia, China, Indonesia, and Vietnam. Hemozoin deposition was confirmed in 44% of all examined monkeys. Monkeys from Indonesia showed the highest incidence of hemozoin deposition (approx. 80%). A high prevalence of Plasmodium infection in laboratory monkeys was also confirmed with polymerase chain reaction (PCR) by using Plasmodium genus-specific primers. Although Japan is not a country with endemic malaria, it is important to be aware of the prevalence and potential impact of background infection with Plasmodium spp. and recrudescence of symptomatic malaria in imported laboratory monkeys on pharmaceutical toxicity studies.

7.
Mol Med Rep ; 11(2): 995-1003, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25369780

RESUMO

Vitamin A deficiency (VAD) caused by malnutrition and certain intestinal diseases induces visual impairments, including night blindness and photoreceptor cell dysfunction as indicated by reduced a­ and b­waves in an electroretinogram (ERG). The effects of VAD on the inner retinal layer cells, including amacrine and ganglion cells, remain to be elucidated. The functions of these cells are reflected in oscillatory potentials (OPs), another component of the ERG. The present study investigated inner retinal layer cell function in VAD rats by analyzing OPs. In the present study, VAD was induced by feeding Brown Norway rats a vitamin A deficient diet for 10 weeks. A reduced body weight and peri­papillary opacification indicative of papilledema without histopathological alterations were observed, which are considered early symptoms of VAD. At this stage, the ERG revealed reduced OPs as well as a­ and b­waves at various intensities of light stimulation. Further analysis indicated that the ratio of the alterations in OPs was more significant than those of a­ and b­waves. After 5 weeks of recovery, these changes returned to control levels. These results suggest that OPs are the most sensitive and early marker of VAD­associated visual impairment in the ERG.


Assuntos
Eletrorretinografia/métodos , Transtornos da Visão/sangue , Deficiência de Vitamina A/sangue , Animais , Masculino , Oscilometria , Ratos , Ratos Endogâmicos BN , Retina/metabolismo , Transtornos da Visão/diagnóstico , Deficiência de Vitamina A/complicações
8.
Development ; 138(19): 4207-17, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21896631

RESUMO

During meiosis, specific histone modifications at pericentric heterochromatin (PCH), especially histone H3 tri- and dimethylation at lysine 9 (H3K9me3 and H3K9me2, respectively), are required for proper chromosome interactions. However, the molecular mechanism by which H3K9 methylation mediates the synapsis is not yet understood. We have generated a Cbx3-deficient mouse line and performed comparative analysis on Suv39h1/h2-, G9a- and Cbx3-deficient spermatocytes. This study revealed that H3K9me2 at PCH depended on Suv39h1/h2-mediated H3K9me3 and its recognition by the Cbx3 gene product HP1γ. We further found that centromere clustering and synapsis were commonly affected in G9a- and Cbx3-deficient spermatocytes. These genetic observations suggest that HP1γ/G9a-dependent PCH-mediated centromere clustering is an axis for proper chromosome interactions during meiotic prophase. We propose that the role of the HP1γ/G9a axis is to retain centromeric regions of unpaired homologous chromosomes in close alignment and facilitate progression of their pairing in early meiotic prophase. This study also reveals considerable plasticity in the interplay between different histone modifications and suggests that such stepwise and dynamic epigenetic modifications may play a pivotal role in meiosis.


Assuntos
Proteínas Cromossômicas não Histona/genética , Pareamento Cromossômico , Histona-Lisina N-Metiltransferase/genética , Histonas/química , Meiose , Animais , Centrômero/ultraestrutura , Homólogo 5 da Proteína Cromobox , Proteínas Cromossômicas não Histona/fisiologia , Epigênese Genética , Feminino , Histona-Lisina N-Metiltransferase/fisiologia , Masculino , Metilação , Camundongos , Camundongos Knockout , Microscopia de Fluorescência/métodos , Modelos Genéticos , Espermatócitos/citologia
9.
Biochem Biophys Res Commun ; 361(1): 109-15, 2007 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-17644066

RESUMO

Gene trapping is a powerful method for identifying novel genes and for analyzing their functions. It is, however, difficult to select trapped genes on the basis of their function. To identify genes regulated by transcription factors that are important in the mesodermal formation, we selected trapped ES clones by infection of adenoviral vectors expressing Pax1, Brachyury, and Foxa2. Among 366 trapped genes, seven seemed to be controlled by these transcription factors in the first screening. The trapped genes were identified by 5' RACE, and a Northern blotting revealed that expressions of three trapped genes were regulated by these transcription factors. Expression patterns of Cx43 and HP1gamma implicated their functional relationships to Foxa2 in the formation of the notochord and the neural tube. Furthermore, Wtap mutant mice derived from the trapped clone showed defects in the mesendoderm formation. Our results indicate that trapped ES clones could be selected effectively using transcription factors.


Assuntos
Regulação da Expressão Gênica , Mutagênese , Fatores de Transcrição/genética , Adenoviridae/genética , Animais , Proteínas de Transporte/genética , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos/metabolismo , Células-Tronco Embrionárias/metabolismo , Proteínas Fetais/genética , Proteínas Fetais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Vetores Genéticos , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Camundongos , Camundongos Mutantes , Proteínas Nucleares/genética , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Fenótipo , Fatores de Processamento de RNA , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...