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1.
J Med Chem ; 60(14): 6337-6352, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28692292

RESUMO

Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.


Assuntos
Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Substâncias Protetoras/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolinas/química , Triazóis/química , Acetaminofen , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Substâncias Protetoras/síntese química , Substâncias Protetoras/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia
2.
Melanoma Res ; 26(2): 117-24, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26684062

RESUMO

Melanoma is a type of cancer arising from the melanocytes, which are the cells that make up the pigment melanin and are derived from the neural crest. There is no particularly effective therapy once the disease is metastatic, highlighting the need for discovery of novel potent agents. In this investigation, we adopted a zebrafish embryonic pigmentation model to identify antimelanoma agents by screening an in-house small molecule library. With this assay, we found that a small molecule compound, SKLB226, blocked zebrafish pigmentation and pigment cell migration. Mechanism of action studies showed that SKLB226 downregulated MITF mRNA level in both zebrafish embryos and mammalian melanoma cells. Further studies showed that it could efficiently suppress the viability and migration of mammalian melanoma cells. In summary, SKLB226 can be used as a chemical tool to study melanocyte development as well as an antimelanoma lead compound that should be subjected to further structural optimization.


Assuntos
Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Fator de Transcrição Associado à Microftalmia/biossíntese , Neoplasias Cutâneas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Peixe-Zebra
3.
Mol Divers ; 18(2): 403-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24515340

RESUMO

Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an IC(50) value of 7 nM.


Assuntos
Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Células Hep G2 , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade
4.
J Med Chem ; 56(4): 1641-55, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23362959

RESUMO

We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.


Assuntos
Antineoplásicos/síntese química , Leucemia Mieloide Aguda/tratamento farmacológico , Pirazóis/síntese química , Pirimidinas/síntese química , Ureia/análogos & derivados , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Animais Geneticamente Modificados , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Transplante de Neoplasias , Compostos de Fenilureia , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Transplante Heterólogo , Ureia/síntese química , Ureia/química , Ureia/metabolismo , Peixe-Zebra , Tirosina Quinase 3 Semelhante a fms/metabolismo
5.
Eur J Med Chem ; 56: 30-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22944772

RESUMO

Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC(50) value of 78 nM.


Assuntos
Caseína Quinase I/antagonistas & inibidores , Diaminas/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Caseína Quinase I/metabolismo , Diaminas/síntese química , Diaminas/química , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
6.
J Med Chem ; 55(8): 3852-66, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22452518

RESUMO

Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinazolinas/uso terapêutico , Tiadiazóis/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Camundongos , Compostos de Fenilureia/síntese química , Quinazolinas/síntese química , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 4): o754, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21754051

RESUMO

In the title compound, C(11)H(14)N(2)O(3), an inter-molecular inter-action between a nitro group O atom and a neighboring benzene ring helps to stabilize the crystal structure [N⋯centroid = 3.933 (2) Å]. No classical hydrogen bonds are observed in the crystal packing.

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