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1.
Nat Methods ; 16(11): 1087-1093, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31659326

RESUMO

Gene knock outs (KOs) are efficiently engineered through CRISPR-Cas9-induced frameshift mutations. While the efficiency of DNA editing is readily verified by DNA sequencing, a systematic understanding of the efficiency of protein elimination has been lacking. Here we devised an experimental strategy combining RNA sequencing and triple-stage mass spectrometry to characterize 193 genetically verified deletions targeting 136 distinct genes generated by CRISPR-induced frameshifts in HAP1 cells. We observed residual protein expression for about one third of the quantified targets, at variable levels from low to original, and identified two causal mechanisms, translation reinitiation leading to N-terminally truncated target proteins or skipping of the edited exon leading to protein isoforms with internal sequence deletions. Detailed analysis of three truncated targets, BRD4, DNMT1 and NGLY1, revealed partial preservation of protein function. Our results imply that systematic characterization of residual protein expression or function in CRISPR-Cas9-generated KO lines is necessary for phenotype interpretation.


Assuntos
Sistemas CRISPR-Cas/genética , Técnicas de Inativação de Genes , Proteínas de Ciclo Celular/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Éxons , Humanos , Mutação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética , Fatores de Transcrição/genética
2.
Angew Chem Int Ed Engl ; 55(38): 11382-6, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27530368

RESUMO

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.

3.
Nature ; 440(7084): 631-6, 2006 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-16429126

RESUMO

Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. Here we report the first genome-wide screen for complexes in an organism, budding yeast, using affinity purification and mass spectrometry. Through systematic tagging of open reading frames (ORFs), the majority of complexes were purified several times, suggesting screen saturation. The richness of the data set enabled a de novo characterization of the composition and organization of the cellular machinery. The ensemble of cellular proteins partitions into 491 complexes, of which 257 are novel, that differentially combine with additional attachment proteins or protein modules to enable a diversification of potential functions. Support for this modular organization of the proteome comes from integration with available data on expression, localization, function, evolutionary conservation, protein structure and binary interactions. This study provides the largest collection of physically determined eukaryotic cellular machines so far and a platform for biological data integration and modelling.


Assuntos
Proteoma/metabolismo , Proteômica , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Genoma Fúngico , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Fases de Leitura Aberta/genética , Fenótipo , Proteoma/química , Proteoma/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética
4.
Nat Cell Biol ; 6(2): 97-105, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14743216

RESUMO

Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa B, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.


Assuntos
Proteínas de Drosophila , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Chaperoninas , Cromatografia de Afinidade/métodos , Ativação Enzimática , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Proteínas I-kappa B/isolamento & purificação , Proteínas I-kappa B/metabolismo , MAP Quinase Quinase Quinase 3 , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Substâncias Macromoleculares , Espectrometria de Massas/métodos , Modelos Biológicos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , NF-kappa B/genética , NF-kappa B/isolamento & purificação , Proteoma/análise , Interferência de RNA , Receptores do Fator de Necrose Tumoral/metabolismo , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/isolamento & purificação , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
5.
J Med Chem ; 64(15): 10742-10771, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34232650

RESUMO

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Piridinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
6.
J Med Chem ; 63(17): 9070-9092, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32691591

RESUMO

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.


Assuntos
Amidas/síntese química , Desenho de Fármacos , Fatores de Transcrição/antagonistas & inibidores , Amidas/química , Amidas/metabolismo , Animais , Derivados de Benzeno/química , Sítios de Ligação , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Cristalografia por Raios X , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Domínios Proteicos , Teoria Quântica , Ratos , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
7.
ACS Med Chem Lett ; 11(8): 1581-1587, 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32832027

RESUMO

Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.

8.
J Med Chem ; 63(11): 5816-5840, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32410449

RESUMO

Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the n-butyl group as an atypical KAc methyl mimetic allowed generation of 31 (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The n-butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.


Assuntos
Proteínas Cromossômicas não Histona/antagonistas & inibidores , Lisina/química , Piridazinas/química , Fatores de Transcrição/antagonistas & inibidores , Sítios de Ligação , Proteínas Cromossômicas não Histona/metabolismo , Cristalografia por Raios X , Humanos , Ligantes , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína , Piridazinas/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
9.
J Med Chem ; 63(17): 9093-9126, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32702236

RESUMO

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.


Assuntos
Anti-Inflamatórios/química , Ligantes , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Amidas/química , Amidas/metabolismo , Amidas/farmacocinética , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Cristalografia por Raios X , Cães , Meia-Vida , Humanos , Ligação de Hidrogênio , Masculino , Simulação de Dinâmica Molecular , Domínios Proteicos , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
10.
Science ; 368(6489): 387-394, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32193360

RESUMO

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Histona Acetiltransferases/antagonistas & inibidores , Fatores Imunológicos/farmacologia , Terapia de Alvo Molecular , Fatores de Transcrição/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Histona Acetiltransferases/química , Histona Acetiltransferases/genética , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Fatores Imunológicos/química , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Domínios Proteicos/efeitos dos fármacos , Fatores de Transcrição/química , Fatores de Transcrição/genética
11.
Epileptic Disord ; 21(1): 112-116, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767894

RESUMO

Dynamin-1-like protein (DNM1L) gene variants have been linked to childhood refractory epilepsy, developmental delay, encephalopathy, microcephaly, and progressive diffuse cerebral atrophy. However, only a few cases have been reported in the literature and there is still a limited amount of information about the symptomatology and pathophysiology associated with pathogenic variants of DNM1L. We report a 10-year-old girl with a one-year history of mild learning disorder and absence seizures who presented with new-onset focal status epilepticus which progressed to severe encephalopathy and asymmetric hemispheric cerebral atrophy. Differential diagnosis included mitochondrial disease, Rasmussen's encephalitis, and autoimmune encephalitis. Disease progressed from one hemisphere to the other despite anti-seizure medications, hemispherectomy, vagus nerve stimulator, ketogenic diet, and immunomodulators. Continued cerebral atrophy and refractory seizures evolved until death four years after initial presentation. Post-mortem whole-exome sequencing revealed a pathogenic DNM1L variant. This paper presents a novel case of adolescent-onset DNM1L-related intractable epilepsy and encephalopathy.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Epilepsia Resistente a Medicamentos , Encefalite , GTP Fosfo-Hidrolases/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Mitocondriais/genética , Adolescente , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Progressão da Doença , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/imunologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Dinaminas , Encefalite/diagnóstico , Encefalite/genética , Encefalite/imunologia , Encefalite/fisiopatologia , Evolução Fatal , Feminino , Humanos
12.
J Med Chem ; 62(16): 7506-7525, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31398032

RESUMO

The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/antagonistas & inibidores , Proteínas de Ligação a DNA/antagonistas & inibidores , Desenho de Fármacos , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Domínios Proteicos , Bibliotecas de Moléculas Pequenas/farmacologia , ATPases Associadas a Diversas Atividades Celulares/química , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Fenômenos Biofísicos , Domínio Catalítico , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
13.
J Med Chem ; 61(18): 8321-8336, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30226378

RESUMO

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/antagonistas & inibidores , Proteínas de Ligação a DNA/antagonistas & inibidores , Descoberta de Drogas , Proteínas Nucleares/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Ciclo Celular , Humanos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Domínios Proteicos , Relação Estrutura-Atividade
14.
J Med Chem ; 60(2): 695-709, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28002667

RESUMO

p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.


Assuntos
Histona Acetiltransferases/química , Sondas Moleculares/química , Piperidinas/química , Piridazinas/química , Fatores de Transcrição de p300-CBP/química , Animais , Permeabilidade da Membrana Celular , Humanos , Membranas Artificiais , Camundongos , Sondas Moleculares/síntese química , Piperidinas/síntese química , Domínios Proteicos , Piridazinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade
15.
ACS Med Chem Lett ; 7(6): 552-7, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326325

RESUMO

The BRPF (Bromodomain and PHD Finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. A selective benzimidazolone BRPF1 inhibitor showing micromolar activity in a cellular target engagement assay was recently described. Herein, we report the optimization of this series leading to the identification of a superior BRPF1 inhibitor suitable for in vivo studies.

16.
J Med Chem ; 59(4): 1425-39, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-25856009

RESUMO

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.


Assuntos
Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Fatores de Transcrição/química
17.
J Med Chem ; 58(15): 6151-78, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26230603

RESUMO

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Proteínas de Ligação a DNA/antagonistas & inibidores , Naftiridinas/química , Naftiridinas/farmacologia , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/química , Proteínas de Ligação a DNA/química , Modelos Moleculares , Estrutura Molecular
18.
J Med Chem ; 58(14): 5649-73, 2015 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-26155854

RESUMO

Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Adenosina Trifosfatases/metabolismo , Sequência de Aminoácidos , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Quinolonas/química , Quinolonas/farmacologia
19.
J Child Neurol ; 18(1): 26-34, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12661935

RESUMO

The purpose of this article is to describe outcomes of intrathecal baclofen therapy for 29 patients with cerebral palsy, focusing on impairments, functional limitations, and disability. Patients received individualized rehabilitation and were followed up to 24 months. The primary outcome measures were the Ashworth Scale and the functional skills and caregiver assistance scales of the Pediatric Evaluation of Disability Inventory (PEDI). Ashworth Scale scores were significantly reduced (P < or = .0005). All areas of functional skills and caregiver assistance improved. Comparing groups of adults and patients less than 18 years, there were no significant differences, but there was a relationship between age and dose. Comparing groups of patients in high and low levels of independent functional mobility, no significant differences were found. These results provide suggestive evidence that the combination of intrathecal baclofen therapy and rehabilitation has positive effects across the dimensions of disablement. This study serves as a basis for high-level scientific studies of these effects.


Assuntos
Atividades Cotidianas/classificação , Baclofeno/administração & dosagem , Paralisia Cerebral/tratamento farmacológico , Exame Neurológico/efeitos dos fármacos , Adolescente , Adulto , Baclofeno/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Avaliação da Deficiência , Feminino , Humanos , Bombas de Infusão Implantáveis , Injeções Espinhais , Masculino , Espasticidade Muscular/tratamento farmacológico , Avaliação de Processos e Resultados em Cuidados de Saúde , Modalidades de Fisioterapia
20.
ACS Med Chem Lett ; 5(11): 1190-5, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25408830

RESUMO

The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain.

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