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1.
J Med Chem ; 59(3): 1078-101, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26796641

RESUMO

The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.


Assuntos
Aminopiridinas/farmacologia , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/farmacologia , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Disponibilidade Biológica , Células CACO-2 , Quinase 8 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Cães , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Ratos , Ratos Wistar , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Solubilidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Med Chem ; 58(4): 1717-35, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25680029

RESUMO

WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Luciferases/antagonistas & inibidores , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Compostos de Espiro/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Bioensaio/métodos , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Luciferases/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Med Chem ; 56(22): 9122-35, 2013 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-24195668

RESUMO

Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Desenho de Fármacos , Imidazóis/química , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Aurora Quinase A/química , Aurora Quinase A/metabolismo , Aurora Quinase B/química , Aurora Quinase B/metabolismo , Domínio Catalítico , Estabilidade de Medicamentos , Células HCT116 , Humanos , Imidazóis/metabolismo , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Especificidade por Substrato
4.
J Med Chem ; 55(20): 8721-34, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-23043539

RESUMO

Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.


Assuntos
Antineoplásicos/síntese química , Imidazóis/síntese química , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Purinas/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinase A , Aurora Quinase B , Aurora Quinases , Disponibilidade Biológica , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Mutação , Transplante de Neoplasias , Purinas/química , Purinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transplante Heterólogo , Tirosina Quinase 3 Semelhante a fms/genética
5.
J Biol Chem ; 285(50): 39348-58, 2010 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-20880844

RESUMO

Cellular stress in early mitosis activates the antephase checkpoint, resulting in the decondensation of chromosomes and delayed mitotic progression. Checkpoint with forkhead-associated and RING domains (CHFR) is central to this checkpoint, and its activity is ablated in many tumors and cancer cell lines through promoter hypermethylation or mutation. The interaction between the PAR-binding zinc finger (PBZ) of CHFR and poly(ADP-ribose) (PAR) is crucial for a functional antephase checkpoint. We determined the crystal structure of the cysteine-rich region of human CHFR (amino acids 425-664) to 1.9 Å resolution, which revealed a multizinc binding domain of elaborate topology within which the PBZ is embedded. The PBZ of CHFR closely resembles the analogous motifs from aprataxin-like factor and CG1218-PA, which lie within unstructured regions of their respective proteins. Based on co-crystal structures of CHFR bound to several different PAR-like ligands (adenosine 5'-diphosphoribose, adenosine monophosphate, and P(1)P(2)-diadenosine 5'-pyrophosphate), we made a model of the CHFR-PAR interaction, which we validated using site-specific mutagenesis and surface plasmon resonance. The PBZ motif of CHFR recognizes two adenine-containing subunits of PAR and the phosphate backbone that connects them. More generally, PBZ motifs may recognize different numbers of PAR subunits as required to carry out their functions.


Assuntos
Adenosina Difosfato Ribose/química , Proteínas de Ciclo Celular/química , Proteínas de Neoplasias/química , Difosfato de Adenosina/química , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X/métodos , Humanos , Ligantes , Mitose , Dados de Sequência Molecular , Proteínas de Ligação a Poli-ADP-Ribose , Ligação Proteica , Estrutura Terciária de Proteína , Ressonância de Plasmônio de Superfície , Temperatura , Ubiquitina-Proteína Ligases , Zinco/química , Dedos de Zinco
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