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BACKGROUND: American Indian and Alaska Native (AI/AN) breast cancer survivors experience disparities in breast cancer incidence and age-adjusted mortality compared with non-Hispanic white (NHW) breast cancer survivors. In addition, mortality-to-incidence rates indicate that AI/ANs continue to have the poorest survival from breast cancer compared with other racial groups. "Native American Cancer Education for Survivors" (NACES) is a cultural education and support intervention for AI/AN patients with cancer that collects data from voluntary participants through the NACES quality-of-life (QOL) survey regarding their cancer experience and survivor journey. METHODS: Data from the NACES QOL survey were analyzed to determine whether barriers accessing and during initial cancer treatment impacted QOL domains for AI/AN cancer survivors. Exploratory analyses of selected variables were conducted and were followed by Kruskal-Wallis tests to determine whether these barriers influenced survivorship QOL for AI/AN breast cancer survivors. RESULTS: AI/AN breast cancer survivors' social QOL was significantly affected by barriers to accessing cancer treatment. Many respondents experienced barriers, including a lack of cancer care at local clinics and the distance traveled to receive cancer care. During treatment, too much paperwork and having to wait too long in the clinic for cancer care were the most frequently reported barriers. CONCLUSIONS: Treatment barriers influence AI/AN breast cancer survivors' social QOL. Mediating these barriers is crucial to ameliorating AI/AN survivors' disparities when accessing and completing cancer treatment and improving survivorship QOL. Cancer 2017;123:861-68. © 2016 American Cancer Society.
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Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Accesibilidad a los Servicios de Salud , Sobrevivientes , Adulto , Anciano , Neoplasias de la Mama/patología , Femenino , Humanos , Indígenas Norteamericanos , Persona de Mediana Edad , Calidad de Vida , Análisis de Supervivencia , Estados Unidos/epidemiología , Población BlancaRESUMEN
INTRODUCTION: Inclusion-body myositis (IBM) is a late-onset idiopathic inflammatory myopathy associated with selective and progressive muscle weakness and atrophy. Current clinical management of IBM is largely supportive due to its uncertain etiology and lack of effective treatment. Establishing a consensus of opinion on questions relating to diagnosis and management of IBM is expected to help reduce inconsistencies in the care and resources allocated to those living with this condition. METHODS: A protocol has been developed to produce best practice clinical guidelines for IBM based on a combination of published research and expert consensus. CONCLUSIONS: In this study we describe the proposed protocol for developing methods for producing robust and transparent clinical guidance on aspects of diagnosis, drug treatment, physical and practical management, respiration, nutrition and cardiac management, psychosocial management, and multidisciplinary care.
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Miositis por Cuerpos de Inclusión/diagnóstico , Miositis por Cuerpos de Inclusión/terapia , Guías de Práctica Clínica como Asunto/normas , Ensayos Clínicos como Asunto/métodos , Humanos , Miositis/diagnóstico , Miositis/terapiaRESUMEN
The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.
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Administración Intravenosa , Animales , Administración Oral , Ratones , Relación Estructura-Actividad , Humanos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Estructura MolecularRESUMEN
TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT's intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.
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Activación de Linfocitos , Linfocitos Infiltrantes de Tumor , Humanos , Microscopía , Receptores Inmunológicos/genética , Transducción de SeñalRESUMEN
This paper compares quality of life (QOL) outcomes between Native American and non-Native cancer survivors. Native Patient Navigators helped Native cancer patients complete a 114-item QOL survey and access survivorship information available on the NACES website. The survey was modified from Ferrell et. al's QOL measure and assessed the four domains of cancer survivorship: physical, psychological, social, and spiritual. Findings from Native survivors were compared to Ferrell's findings. This is the first time that QOL outcomes have been compared between Native and Non-Native cancer survivors. Natives scored lower for physical and social QOL, the same for psychological QOL, and higher for spiritual QOL in comparison to non-Natives. Overall QOL scores were the same. Although this is the largest sample of Native cancer survivors reported in peer-reviewed manuscripts, these Native survivorship data are based on a self-selected group and it is unknown if the findings are generalizable to others.
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Indígenas Norteamericanos/psicología , Neoplasias/epidemiología , Calidad de Vida/psicología , Estrés Psicológico/psicología , Sobrevivientes/psicología , Adaptación Psicológica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Encuestas Epidemiológicas , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Neoplasias/psicología , Psicometría , Sobrevivientes/estadística & datos numéricos , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Adult hippocampal neurogenesis in the developmental process of generating and integrating new neurons in the hippocampus during adulthood and is a unique form of structural plasticity with enormous potential to modulate neural circuit function and behaviour. Dysregulation of this process is strongly linked to stress-related neuropsychiatric conditions such as anxiety and depression, and efforts have focused on unravelling the contribution of adult-born neurons in regulating stress response and recovery. Chronic stress has been shown to impair this process, whereas treatment with clinical antidepressants was found to enhance the production of new neurons in the hippocampus. However, the precise role of adult hippocampal neurogenesis in mediating the behavioural response to chronic stress is not clear and whether these adult-born neurons buffer or increase susceptibility to stress-induced mood-related maladaptation remains one of the controversial issues. In this review, we appraise evidence probing the causal role of adult hippocampal neurogenesis in the regulation of emotional behaviour in rodents. We find that the relationship between adult-born hippocampal neurons and stress-related mood disorders is not linear, and that simple subtraction or addition of these neurons alone is not sufficient to lead to anxiety/depression or have antidepressant-like effects. We propose that future studies examining how stress affects unique properties of adult-born neurons, such as the excitability and the pattern of connectivity during their critical period of maturation will provide a deeper understanding of the mechanisms by which these neurons contribute to functional outcomes in stress-related mood disorders.
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The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.
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Lisina , Factores de Transcripción , Humanos , Lisina/metabolismo , Ligandos , Dominios Proteicos , Histonas/metabolismoRESUMEN
INTRODUCTION: PROTACs represent a novel class of heterobifunctional molecules that simultaneously bind to a target protein and to an E3 ligase complex, resulting in the transfer of ubiquitin and initiating a process ultimately causing the proteasomal degradation of the target protein. This mechanism of action imbues PROTACs with the ability to modulate target biology in unique ways compared to inhibitors, and the development of PROTACs as therapeutic agents is expected to result in new medicines to treat multiple diseases. AREAS COVERED: This review includes published PCT (WO) patent applications covering January 2013 through June 2020. Only English-language patent applications with exemplified PROTACs reported to degrade a target protein(s) were deemed in scope, and the definition of 'PROTAC' was restricted to a bifunctional molecule which contains a discrete binding element for a specific degradation target(s), as well as a separate discrete E3 ligase-binding moiety. EXPERT OPINION: Delivering on the enormous potential of PROTACs will require the development of PROTAC medicines that are differentiated from traditional small-molecule inhibitors. The modular composition of PROTACs affords both opportunities and challenges in securing robust intellectual property, and we envision that requirements for novelty are likely to evolve as this area matures.
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Desarrollo de Medicamentos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/metabolismo , Animales , Diseño de Fármacos , Humanos , Patentes como Asunto , UbiquitinaciónRESUMEN
A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis.
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Amidinas/farmacología , Antiparasitarios/farmacología , Desarrollo de Medicamentos , Leishmania mexicana/efectos de los fármacos , Pentamidina/farmacología , Amidinas/química , Antiparasitarios/síntesis química , Antiparasitarios/química , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/efectos de los fármacos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Pentamidina/síntesis química , Pentamidina/química , Relación Estructura-ActividadRESUMEN
The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.
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Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Imidazoles/uso terapéutico , Proteínas Nucleares/antagonistas & inhibidores , Quinolinas/uso terapéutico , Factores de Transcripción/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Artritis/inducido químicamente , Colágeno , Cristalografía por Rayos X , Perros , Femenino , Imidazoles/síntesis química , Imidazoles/metabolismo , Masculino , Ratones , Estructura Molecular , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Unión Proteica , Dominios Proteicos , Quinolinas/síntesis química , Quinolinas/metabolismo , Ratas Endogámicas Lew , Ratas Wistar , Relación Estructura-Actividad , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
Seagrasses have global distribution and are highly productive and economically valuable habitats. They are sensitive and vulnerable to a range of human-induced pressures, including ongoing exposure to marine litter, such as microplastic particles (<5â¯mm). In this study, a Zostera marina bed in Deerness Sound, Orkney was selected to determine whether microplastics accumulate in seagrass beds and adhere to seagrass blades. Sediment, seagrass blade, biota and seawater samples were collected. 280 microplastic particles (0.04 to 3.95â¯mm (meanâ¯=â¯0.95â¯mm⯱â¯0.05 SE)) were observed in 94% of samples collected (nâ¯=â¯111). These were visually categorised into type (fibre, flake, fragment) and colour, and 50 were successfully identified as plastic using ATR-FTIR. Fibres contributed >50% of the total microplastics observed across all samples. This is the first known study on Z. marina to describe microplastic loading within a seagrass bed and to identify microplastic adherence to seagrass blades.
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Zosteraceae , Ecosistema , Microplásticos , Plásticos , EscociaRESUMEN
The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
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Ensayos Analíticos de Alto Rendimiento/métodos , Proteínas/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Quimiocina CCL2/biosíntesis , Cristalografía por Rayos X , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Masculino , Ratones , Modelos Moleculares , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Bibliotecas de Moléculas PequeñasRESUMEN
The biphenyl amides (BPAs) are a novel series of p38 MAP kinase inhibitors. The discovery of the series through structure-based focused screening is described, and the binding mode of the compounds is explained with reference to X-ray crystal structures.
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Amidas/farmacología , Compuestos de Bifenilo/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Amidas/química , Amidas/metabolismo , Compuestos de Bifenilo/química , Compuestos de Bifenilo/metabolismo , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model.
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Amidas/farmacología , Compuestos de Bifenilo/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/farmacocinética , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Oxadiazoles/química , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
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Amidas/síntesis química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Amidas/sangre , Amidas/química , Aminoácidos/genética , Aminoácidos/metabolismo , Sitios de Unión , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Lipopolisacáridos/farmacología , Conformación Molecular , Estructura Molecular , Naftalenos/farmacología , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.
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Benzamidas/síntesis química , Benzamidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Benzamidas/sangre , Benzamidas/química , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Conformación Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/química , RatasRESUMEN
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.
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Histona Acetiltransferasas/química , Sondas Moleculares/química , Piperidinas/química , Piridazinas/química , Factores de Transcripción p300-CBP/química , Animales , Permeabilidad de la Membrana Celular , Humanos , Membranas Artificiales , Ratones , Sondas Moleculares/síntesis química , Piperidinas/síntesis química , Dominios Proteicos , Piridazinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
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Indazoles/química , Oxazoles/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Enfermedades Respiratorias/tratamiento farmacológico , Sulfonamidas/química , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Femenino , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Indoles , Isoenzimas/antagonistas & inhibidores , Masculino , Microsomas/metabolismo , Simulación del Acoplamiento Molecular , Ovalbúmina/inmunología , Oxazoles/farmacocinética , Oxazoles/farmacología , Piperazinas , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Conejos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Células Th2/inmunologíaRESUMEN
Visual inspection of X-ray images of luggage is a time-pressured task that typically shows large initial training effects, but there exists a paucity of models capable of evaluating performance and speed concurrently. In the present study, visual inspection ability during learning was modeled using Drury's two-component inspection model (TCM; Drury, 1975) in a laboratory experiment involving 12 younger (mean age=20.8 years) and 12 older (mean age=60.0 years) naive participants undertaking a simplified luggage search task. Model fits and assumptions were found to be reliable and accurately reflected improvement with training for decision time, although neither search nor decision components of the model individually showed a significant effect of age. The decision component of the model showed larger improvement with training than did the search component, and stopping-time policy accurately reflected the improvements found between ages and within training levels. The TCM is a useful supplement to detection theory when speed of performance is a factor.
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Envejecimiento/psicología , Investigación Conductal/métodos , Desempeño Psicomotor , Conducta de Elección , Femenino , Humanos , Aprendizaje , Masculino , Persona de Mediana Edad , Modelos Psicológicos , Enseñanza , Adulto JovenRESUMEN
p38alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFalpha and IL-1beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38alpha/beta inhibitors using crystal structures of our inhibitors bound to p38alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.