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1.
Toxicol Appl Pharmacol ; 269(1): 1-7, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23466428

RESUMO

Polo like kinase 2 (PLK2) phosphorylates α-synuclein and is considered a putative therapeutic target for Parkinson's disease. Several lines of evidence indicate that PLK2 is involved with proper centriole duplication and cell cycle regulation, inhibition of which could impact chromosomal integrity during mitosis. The objectives of the series of experiments presented herein were to assess whether specific inhibition of PLK2 is genotoxic and determine if PLK2 could be considered a tractable pharmacological target for Parkinson's disease. Several selective PLK2 inhibitors, ELN 582175 and ELN 582646, and their inactive enantiomers, ELN 582176 and ELN 582647, did not significantly increase the number of micronuclei in the in vitro micronucleus assay. ELN 582646 was administered to male Sprague Dawley rats in an exploratory 14-day study where flow cytometric analysis of peripheral blood identified a dose-dependent increase in the number of micronucleated reticulocytes. A follow-up investigative study demonstrated that ELN 582646 administered to PLK2 deficient and wildtype mice significantly increased the number of peripheral micronucleated reticulocytes in both genotypes, suggesting that ELN 582646-induced genotoxicity is not through the inhibition of PLK2. Furthermore, significant reduction of retinal phosphorylated α-synuclein levels was observed at three non-genotoxic doses, additional data to suggest that pharmacological inhibition of PLK2 is not the cause of the observed genotoxicity. These data, in aggregate, indicate that PLK2 inhibition is a tractable CNS pharmacological target that does not cause genotoxicity at doses and exposures that engage the target in the sensory retina.


Assuntos
Aberrações Cromossômicas/induzido quimicamente , Linfócitos/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Inibidores de Proteínas Quinases/toxicidade , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Reticulócitos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Citometria de Fluxo , Células HEK293 , Humanos , Linfócitos/enzimologia , Linfócitos/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testes para Micronúcleos , Fosforilação , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Reticulócitos/enzimologia , Reticulócitos/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Medição de Risco , Fatores de Tempo , Transfecção , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
2.
Bioorg Med Chem Lett ; 23(9): 2743-9, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23522834

RESUMO

Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Encéfalo/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/síntese química , Pteridinas/química , Pteridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Quinase 1 Polo-Like
3.
ChemMedChem ; 8(8): 1295-313, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23794260

RESUMO

Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.


Assuntos
Encéfalo/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , alfa-Sinucleína/metabolismo , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Feminino , Células HEK293 , Meia-Vida , Humanos , Masculino , Camundongos , Simulação de Dinâmica Molecular , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley
4.
PLoS One ; 7(7): e40443, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22792325

RESUMO

TH17 cells enter tissues to facilitate pathogenic autoimmune responses, including multiple sclerosis (MS). However, the adhesion molecules involved in the unique migratory capacity of TH17 cells, into both inflamed and uninflamed tissues remain unclear. Herein, we characterize MCAM (CD146) as an adhesion molecule that defines human TH17 cells in the circulation; following in vitro restimulation of human memory T cells, nearly all of the capacity to secrete IL-17 is contained within the population of cells expressing MCAM. Furthermore, we identify the MCAM ligand as laminin 411, an isoform of laminin expressed within the vascular endothelial basement membranes under inflammatory as well as homeotstatic conditions. Purified MCAM-Fc binds to laminin 411 with an affinity of 27 nM, and recognizes vascular basement membranes in mouse and human tissue. MCAM-Fc binding was undetectable in tissue from mice with targeted deletion of laminin 411, indicating that laminin 411 is a major tissue ligand for MCAM. An anti-MCAM monoclonal antibody, selected for inhibition of laminin binding, as well as soluble MCAM-Fc, inhibited T cell adhesion to laminin 411 in vitro. When administered in vivo, the antibody reduced TH17 cell infiltration into the CNS and ameliorated disease in an animal model of MS. Our data suggest that MCAM and laminin 411 interact to facilitate TH17 cell entry into tissues and promote inflammation.


Assuntos
Plexo Corióideo/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Laminina/fisiologia , Células Th17/fisiologia , Animais , Antígeno CD146/metabolismo , Células CHO , Movimento Celular , Polaridade Celular , Proliferação de Células , Plexo Corióideo/imunologia , Plexo Corióideo/patologia , Cricetinae , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Matriz Extracelular/metabolismo , Feminino , Humanos , Interleucina-17/metabolismo , Interleucina-1beta/fisiologia , Interleucinas/metabolismo , Ligantes , Camundongos , Camundongos Knockout , Ligação Proteica , Células Th17/metabolismo , Interleucina 22
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