Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Leukemia ; 38(1): 82-95, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38007585

RESUMO

We identified activin A receptor type I (ACVR1), a member of the TGF-ß superfamily, as a factor favoring acute myeloid leukemia (AML) growth and a new potential therapeutic target. ACVR1 is overexpressed in FLT3-mutated AML and inhibition of ACVR1 expression sensitized AML cells to FLT3 inhibitors. We developed a novel ACVR1 inhibitor, TP-0184, which selectively caused growth arrest in FLT3-mutated AML cell lines. Molecular docking and in vitro kinase assays revealed that TP-0184 binds to both ACVR1 and FLT3 with high affinity and inhibits FLT3/ACVR1 downstream signaling. Treatment with TP-0184 or in combination with BCL2 inhibitor, venetoclax dramatically inhibited leukemia growth in FLT3-mutated AML cell lines and patient-derived xenograft models in a dose-dependent manner. These findings suggest that ACVR1 is a novel biomarker and plays a role in AML resistance to FLT3 inhibitors and that FLT3/ACVR1 dual inhibitor TP-0184 is a novel potential therapeutic tool for AML with FLT3 mutations.


Assuntos
Leucemia Mieloide Aguda , Humanos , Simulação de Acoplamento Molecular , Mutação , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Apoptose , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/uso terapêutico
2.
Bioconjug Chem ; 26(1): 78-89, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25350602

RESUMO

We report in vitro and in vivo evaluation of a newly designed trifunctional theranostic agent for targeting solid tumors. This agent combines a dendritic wedge with high boron content for boron neutron capture therapy or boron MRI, a monomethine cyanine dye for visible-light fluorescent imaging, and an integrin ligand for efficient tumor targeting. We report photophysical properties of the new agent, its cellular uptake and in vitro targeting properties. Using live animal imaging and intravital microscopy (IVM) techniques, we observed a rapid accumulation of the agent and its retention for a prolonged period of time (up to 7 days) in fully established animal models of human melanoma and murine mammary adenocarcinoma. This macromolecular theranostic agent can be used for targeted delivery of high boron load into solid tumors for future applications in boron neutron capture therapy.


Assuntos
Dendrímeros/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/terapia , Animais , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular , Dendrímeros/metabolismo , Dendrímeros/farmacocinética , Humanos , Integrinas/metabolismo , Ligantes , Camundongos , Neoplasias/patologia , Distribuição Tecidual
3.
Biomed Res Int ; 2014: 273180, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25313354

RESUMO

BACKGROUND: Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients. MATERIALS AND METHODS: To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several cancer cell lines, including multiple myeloma lines. Small-molecule inhibitors of Nek2 were discovered using an in-house library of compounds. We tested the inhibitors on proteasome and cell cycle activity in several cell lines. RESULTS: Proteasome activity was elevated in Nek2-overexpressing cell lines. The Nek2 inhibitors inhibited proteasome activity in these cancer cell lines. Treatment with these inhibitors resulted in inhibition of proteasome-mediated degradation of several cell cycle regulators in HeLa cells, leaving them arrested in G2/M. Combining these Nek2 inhibitors with bortezomib increased the efficacy of bortezomib in decreasing proteasome activity in vitro. Treatment with these novel Nek2 inhibitors successfully mitigated drug resistance in bortezomib-resistant multiple myeloma. CONCLUSION: Nek2 plays a central role in proteasome-mediated cell cycle regulation and in conferring resistance to bortezomib in cancer cells. Taken together, our results introduce Nek2 as a therapeutic target in bortezomib-resistant multiple myeloma.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Ácidos Borônicos/farmacologia , Bortezomib , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Ciclina B/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Quinases Relacionadas a NIMA , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise/efeitos dos fármacos , Pirazinas/farmacologia , Bibliotecas de Moléculas Pequenas/química
4.
Neoplasia ; 16(5): 403-12, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24953177

RESUMO

The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células de Transição/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Neoplasias da Bexiga Urinária/enzimologia , Animais , Western Blotting , Feminino , Humanos , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase Multiplex , Oligopeptídeos/farmacologia , Proto-Oncogene Mas , Piridazinas/farmacologia , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução Genética , Peptídeo Intestinal Vasoativo/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
ACS Med Chem Lett ; 2(12): 907-912, 2011 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-22247788

RESUMO

The receptor tyrosine kinase AXL has emerged in recent years as an potential oncology target due to its over expression in several types of cancers coupled with its ability to promote tumor growth and metastasis. In order to identify small molecule inhibitors of AXL, we built a homology model of its catalytic domain to virtually screen and identify scaffolds displaying an affinity for AXL. Further computational and structure-based design resulted in the synthesis of a series of 2,4,5-trisubstitued pyrimidines which demonstrated potent inhibition of AXL in vitro (IC(50) 19 nM) and strongly inhibited the growth of several pancreatic cell lines.

6.
Inorg Chem ; 45(25): 10172-9, 2006 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-17140224

RESUMO

A new tricarborane building block based on pentaerythritol was prepared for applications in boron neutron capture therapy (BNCT). Its X-ray single-crystal structure revealed a high degree of steric congestion. To enable the attachment of the building block to other moieties, a succinimidyl linker has been introduced at the focal point, and a generation-2 hexacarborane-containing dendron carrying 60 boron atoms has been prepared using a 2,2-bis(hydroxymethyl)propionic acid core.


Assuntos
Compostos de Boro/síntese química , Terapia por Captura de Nêutron de Boro/métodos , Propilenoglicóis/síntese química , Cristalografia por Raios X , Modelos Químicos , Propionatos/química , Estereoisomerismo , Succinimidas/química
7.
Inorg Chem ; 45(19): 7815-20, 2006 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-16961373

RESUMO

New carborane-containing dendrons based on a 2,2-bis(hydroxymethyl)propanoic acid scaffold have been prepared for applications in boron neutron capture therapy. A generation-2 carborane-containing dendron carrying 40 boron atoms was the highest generation synthetically available due to the steric crowding. The structure of this dendron has been simulated by molecular dynamics. A 10-carbon linker carrying a carboxylic group has been installed at the focal point of the dendron to distance the attachment point from the sterically hindered core.


Assuntos
Compostos de Boro/química , Dendrímeros/química , Poliésteres/química , Simulação por Computador , Modelos Moleculares , Estrutura Molecular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...