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1.
Proc Natl Acad Sci U S A ; 111(17): 6461-6, 2014 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-24706880

RESUMO

Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. Reduction in the dendritic spine density is a major alteration that has been reproducibly reported in the cerebral cortex of patients with schizophrenia. Disrupted-in-Schizophrenia-1 (DISC1), a factor that influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, has a regulatory role in the postsynaptic density in association with the NMDA-type glutamate receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration, reminiscent of the synaptic pathology of schizophrenia. Thus, we tested the effects of novel inhibitors to p21-activated kinases (PAKs), major targets of Rac1, on synaptic deterioration elicited by knockdown expression of DISC1. These compounds not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses in culture. One of these PAK inhibitors prevented progressive synaptic deterioration in adolescence as shown by in vivo two-photon imaging and ameliorated a behavioral deficit in prepulse inhibition in adulthood in a DISC1 knockdown mouse model. The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general.


Assuntos
Envelhecimento/patologia , Espinhas Dendríticas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/enzimologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/enzimologia , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridonas/química , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Interferência de RNA/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/fisiopatologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Quinases Ativadas por p21/metabolismo
2.
Proc Natl Acad Sci U S A ; 110(14): 5671-6, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23509247

RESUMO

Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition--including hyperactivity, repetitive behaviors, and seizures--as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor--which we call FRAX486--also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.


Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Citoesqueleto de Actina/fisiologia , Animais , Espinhas Dendríticas/genética , Espinhas Dendríticas/patologia , Relação Dose-Resposta a Droga , Descoberta de Drogas/métodos , Epilepsia Reflexa/tratamento farmacológico , Epilepsia Reflexa/etiologia , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Teste de Desempenho do Rota-Rod , Relação Estrutura-Atividade
3.
Breast Cancer Res ; 17: 59, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25902869

RESUMO

INTRODUCTION: Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase (PAK)1. PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis. METHODS: PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n=980 and 1,108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting. RESULTS: We demonstrate that focal genomic amplification and overexpression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P=1.29×10(-4) and P=0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis. CONCLUSIONS: Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Microtúbulos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Moduladores de Tubulina/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Apoptose/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Docetaxel , Sinergismo Farmacológico , Feminino , Amplificação de Genes , Expressão Gênica , Humanos , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
4.
Bioorg Med Chem Lett ; 22(2): 1237-41, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22182498

RESUMO

The overproduction of nitric oxide during the biological response to inflammation by the nitric oxide synthase (NOS) enzymes have been implicated in the pathology of many diseases. By removal of the amide core from uHTS-derived quinolone 4, a new series highly potent heteroaromatic-aminomethyl quinolone iNOS inhibitors 8 were identified. SAR studies led to identification of piperazine 22 and pyrimidine 32, both of which reduced plasma nitrates following oral dosing in a mouse lipopolysaccharide challenge assay.


Assuntos
Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Quinolonas/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Quinolonas/síntese química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-Atividade
5.
J Am Chem Soc ; 132(6): 1802-3, 2010 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-20095555

RESUMO

A convergent synthesis of (-)-crambidine is reported. The sequence capitalizes on two novel key transformations, including a [4+2] annulation of thioimidates with vinyl carbodiimides and an alkyne hydroamination employing 2-aminopyrimidine nucleophiles.


Assuntos
Alcinos/química , Carbodi-Imidas/química , Guanidina/análogos & derivados , Imidoésteres/química , Pirimidinas/química , Compostos de Espiro/química , Compostos de Espiro/síntese química , Aminação , Guanidina/síntese química , Guanidina/química , Estereoisomerismo
6.
Oncotarget ; 6(4): 1981-94, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25596744

RESUMO

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.


Assuntos
Meningioma/metabolismo , Neurofibromina 2/deficiência , Quinases Ativadas por p21/metabolismo , Animais , Antineoplásicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Doxiciclina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Immunoblotting , Meningioma/genética , Meningioma/terapia , Camundongos SCID , Neurofibromina 2/genética , Piridonas/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , Terapêutica com RNAi , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/genética
7.
Org Lett ; 6(5): 839-41, 2004 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-14986988

RESUMO

N-(phenylthio)-epsilon-caprolactam (1) has been applied as a new promoter for the activation of thioglycosides. This proceeds by the reaction of 1 with trifluoromethansulfonic anhydride, which subsequently activates the thioglycoside for glycosidic bond formation. Notably, the reaction proceeds efficiently at room temperature and is adaptable to our reactivity-based one-pot oligosaccharide synthesis. [reaction: see text]


Assuntos
Lactamas/química , Sulfetos/química , Tioglicosídeos/química , Sequência de Carboidratos , Glicosilação , Dados de Sequência Molecular , Estereoisomerismo
8.
Cancer Res ; 72(22): 5966-75, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22983922

RESUMO

The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of Kras(G12D) mice with either of two distinct small molecule Pak inhibitors (PF3758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Proteínas Proto-Oncogênicas/metabolismo , Piridonas/farmacologia , Pirimidinas/farmacologia , Neoplasias Cutâneas/enzimologia , Quinases Ativadas por p21/biossíntese , Proteínas ras/metabolismo , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Deleção de Genes , Genes ras , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Gradação de Tumores , Estadiamento de Neoplasias , Proteína Oncogênica v-akt/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/deficiência , Quinases Ativadas por p21/genética , Proteínas ras/genética
9.
J Am Chem Soc ; 128(40): 13255-60, 2006 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-17017806

RESUMO

A diastereoselective [4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich polycyclic guanidine cores of the batzelladine alkaloids. Application of this strategy, together with additional key steps such as long-range directed hydrogenation and diastereoselective intramolecular iodo-amination, led to highly convergent total syntheses of (-)-batzelladine D and (+)-batzelladine A with excellent stereocontrol.


Assuntos
Alcaloides/síntese química , Carbodi-Imidas/química , Guanidinas/síntese química , Iminas/química , Pirimidinas/síntese química , Estereoisomerismo
10.
J Am Chem Soc ; 127(19): 6924-5, 2005 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-15884915

RESUMO

A diastereoselective [4+2] annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich tricyclic core of the batzelladine alkaloids. Its application to the asymmetric synthesis of batzelladine D permitted the use of long-range, directed hydrogenation and stereoselective intramolecular iodoamination as additional key steps to establish the remaining stereocenters within the natural product with excellent stereocontrol.


Assuntos
Alcaloides/síntese química , Carbodi-Imidas/química , Guanidina/análogos & derivados , Iminas/química , Compostos de Vinila/química , Alquilação , Guanidina/síntese química , Guanidinas/síntese química , Pirimidinas/síntese química , Estereoisomerismo
11.
Proc Natl Acad Sci U S A ; 100(3): 797-802, 2003 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-12552090

RESUMO

The total synthesis of the sialic acid-containing antigenic epitope fucose GM(1) (Fuc-GM(1)) by an improved reactivity-based one-pot synthetic strategy is reported. Based on a thioglycoside reactivity database, three saccharide building blocks, 3, 4, and 5, were designed and prepared to incorporate a descending order of reactivity toward thiophilic activation. Using the reactivity-based one-pot synthetic method, the fully protected Fuc-GM(1) glycoside 2 was furnished in a facile manner, which was globally deprotected to give the Fuc-GM(1) glycoside 1. In addition, using the promoter system 1-(benzensulfinyl)piperidinetrifluoromethanesulfonic anhydride, the product yield was improved and the reaction time was reduced in comparison with the N-iodosuccinimidetrifluoromethanesulfonic acid- and dimethyl (thiomethyl) sulfonium trifluoromethanesulfonate-promoted systems.


Assuntos
Carcinoma de Células Pequenas/metabolismo , Fucose/química , Neoplasias Pulmonares/metabolismo , Ácido N-Acetilneuramínico/química , Oligossacarídeos/química , Oligossacarídeos/síntese química , Sequência de Carboidratos , Carcinoma de Células Pequenas/imunologia , Dissacarídeos , Epitopos , Neoplasias Pulmonares/imunologia , Dados de Sequência Molecular
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