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1.
J Am Chem Soc ; 139(32): 11184-11196, 2017 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-28648054

RESUMEN

Given the importance of amines in a large number of biologically active natural products, active pharmaceutical ingredients, agrochemicals, and functional materials, the development of efficient C-N bond-forming methods with wide substrate scope continues to be at the frontier of research in synthetic organic chemistry. Here, we present a general and fundamentally new synthetic approach for the direct, transition-metal-free preparation of symmetrical and unsymmetrical diaryl-, arylalkyl-, and dialkylamines that relies on the facile single or double addition of readily available C-nucleophiles to the nitrogen atom of bench-stable electrophilic aminating agents. Practical single and double polarity reversal (i.e., umpolung) of the nitrogen atom is achieved using sterically and electronically tunable ketomalonate-derived imines and oximes. Overall, this novel approach represents an operationally simple, scalable, and environmentally friendly alternative to transition-metal-catalyzed C-N cross-coupling methods that are currently used to access structurally diverse secondary amines.


Asunto(s)
Aminas/química , Carbono/química , Hidrocarburos Aromáticos/química , Nitrógeno/química , Aminación , Aminas/síntesis química , Catálisis , Hidrocarburos Aromáticos/síntesis química , Modelos Moleculares , Estereoisomerismo , Elementos de Transición/química
3.
BJGP Open ; 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39313319

RESUMEN

BACKGROUND: Proton pump inhibitors (PPIs) the most frequently prescribed drug class globally, are often overused. AIM: To assess PPI prescribing practice in England. DESIGN & SETTING: Electronic medical record (EMR) evaluation from 62 primary care GP practices. METHOD: Adult patients on continuous PPI treatment (repeat prescription or≥4 acute prescriptions 6 months before data extraction) were included (August 2021-June 2022) to compare PPI prescribing practices vs National Institute for Health and Care Excellence (GORD and dyspepsia management) and Medicines and Healthcare products Regulatory Agency (clopidogrel-PPI interaction) guidelines. RESULTS: We identified 77,356 patients on continuous PPI treatment. The most common (68%) diagnosis recorded in patients' EMRs and indicated for PPI use was gastroprotection, although 62% had no recorded indication. Of these 62% patients, 40% had no medication review in the preceding year. Among those with diagnoses indicated for≤3 months of PPI therapy (34%), 99% received their first PPI prescription≥3 months previously. Of patients with diagnoses indicated for long-term treatment (4%), 41% had no medication review in the preceding year. Furthermore, 18% of patients using omeprazole or esomeprazole were also prescribed clopidogrel, and 19% of those prescribed treatments associated with gastrointestinal risk (N=14,826) were not prescribed PPIs. CONCLUSION: This study shows that PPI prescribing in England is not in alignment with existing clinical guidelines and highlights the need for appropriate measures to increase awareness of overuse and support deprescribing where appropriate.

4.
J Pers Soc Psychol ; 124(1): 215-235, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36301277

RESUMEN

The purpose of the present research was to test the level of agreement between targets and observers both at any given moment and as the targets' current behavior (assessed as personality states) change across moments. Ninety-seven target participants participated in 22 different activities across 20 1-hour long sessions in a laboratory setting while reporting their current behavior, and their behavior was evaluated by 183 observers (total of 3,493 target self-reports, 2,973 of which had a corresponding observer report from at least one observer). Target-observer and observer-observer agreement was significant for all personality states (and was substantial for extraversion, conscientiousness, and openness to experience), and was observed in different situations, across all situations, and after accounting for normative agreement. The findings from this study-the first to examine within-person agreement on in-person behavioral states-provide evidence that people can accurately report their current behavior, that people agree on changes in behaviors across situations, and by extension that intensive assessment methodologies (such as experience-sampling methodology) have validity as assessments of momentary behavior. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Asunto(s)
Extraversión Psicológica , Personalidad , Humanos , Conducta Social , Autoinforme , Evaluación Ecológica Momentánea
5.
Cell Chem Biol ; 30(10): 1191-1210.e20, 2023 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-37557181

RESUMEN

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Histonas/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Transducción de Señal , Línea Celular Tumoral
6.
Anal Biochem ; 414(2): 179-86, 2011 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-21402045

RESUMEN

The PI3K/AKT signaling pathway has an important regulatory role in cancer cell growth and tumorigenesis. Signal transduction through this pathway requires the assembly and activation of PDK1 and AKT at the plasma membrane. On activation of the pathway, PDK1 and AKT1/2 translocate to the membrane and bind to phosphatidylinositol-(3,4,5)-trisphosphate (PIP(3)) through interaction with their pleckstrin-homology domains. A biochemical method was developed to measure the kinase activity of PDK1 and AKT1/2, utilizing nickel-chelating coated lipid vesicles as a way to mimic the membrane environment. The presence of these vesicles in the reaction buffer enhanced the specific activity of the His-tagged PDK1 (full-length, and the truncated kinase domain) and the activity of the full-length His-tagged AKT1 and AKT2 when assayed in a cascade-type reaction. This enhanced biochemical assay is also suitable for measuring the inhibition of PDK1 by several selective compounds from the carbonyl-4-amino-pyrrolopyrimidine (CAP) series. One of these inhibitors, PF-5168899, was further evaluated using a high content cell-based assay in the presence of CHO cells engineered with GFP-PDK1.


Asunto(s)
Adenina/análogos & derivados , Pruebas de Enzimas/métodos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazinas/farmacología , Transducción de Señal , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Adenina/química , Adenina/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Histidina/genética , Histidina/metabolismo , Humanos , Cinética , Oligopéptidos/genética , Oligopéptidos/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Pirazinas/química , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
7.
Therapie ; 76(6): 567-576, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33589316

RESUMEN

OBJECTIVES: To evaluate adherence after treatment switch from a multiple-tablet regimen (MTR) to a single-tablet regimen (STR) in a national cohort of human immunodeficiency virus (HIV) patients. METHODS: This retrospective observational cohort, with data spanning January 1, 2000 to March 1, 2019, consisted of HIV infected patients receiving treatment from the Veterans Affairs (VA) health system. Patients were required to have a complete MTR regimen after January 1, 2006 and before December 31, 2018 with at least 60 days of treatment. Medical and pharmacy data were analyzed from the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database. Statistical analyses examined differences in adherence when patients switched to a STR. Patients who switched to a STR were propensity score matched to those who never switched. Descriptive statistics and multivariable linear mixed effects models were utilized to evaluate differences in adherence between MTR and STR treatment in both the matched and unmatched samples. RESULTS: A total of 5021 patients met the study criteria, 3906 patients in the MTR only cohort and 1115 patients in the switch to STR cohort. The unmatched cohorts were similar in terms of sex, index year, drug/alcohol abuse, and viral load but differed in terms of race, Charlson comorbidity and mental health conditions. The one to one propensity score matched cohort included 2230 patients, 1115 patients in each cohort. Among patients that switched from a MTR to STR, adherence increased on average from 65.9% to 78.12%. We find overall adherence is higher with STRs than with MTR HIV regimens in both the matched and unmatched sample and adherence declines with time for both STR and MTR regimens. CONCLUSIONS: Switching to a STR is associated with higher adherence compared to MTR among patients with HIV treated with antiretrovirals. However, adherence declines over time with both STR and MTR regimens.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Cumplimiento de la Medicación , Estudios Retrospectivos , Comprimidos/uso terapéutico , Carga Viral
8.
J Med Chem ; 64(3): 1725-1732, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529029

RESUMEN

A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Profármacos/síntesis química , Profármacos/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Linfoma de Células B/tratamiento farmacológico , Ratones , Modelos Moleculares , Profármacos/farmacocinética , Piridonas/farmacocinética , Ratas , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Med Chem ; 64(13): 9056-9077, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34110834

RESUMEN

Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inyecciones Intravenosas , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
10.
Cancer Cell ; 39(10): 1404-1421.e11, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34520734

RESUMEN

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Femenino , Humanos , Masculino , Neoplasias/inmunología
11.
J Med Chem ; 64(1): 644-661, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33356246

RESUMEN

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.


Asunto(s)
Diseño de Fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Animales , Línea Celular , Cromatografía Líquida de Alta Presión/métodos , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética/métodos , Ratones , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Ratas , Espectrometría de Masa por Ionización de Electrospray/métodos
12.
Muscle Nerve ; 41(1): 5-17, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19697368

RESUMEN

Rapid progress in the discovery of motor neuron disease genes in amyotrophic lateral sclerosis, the spinal muscular atrophies, hereditary motor neuropathies, and lethal congenital contracture syndromes is providing new perspectives and insights into the molecular pathogenesis of the motor neuron. Motor neuron disease genes are often expressed throughout the body with essential functions in all cells. A survey of these functions indicates that motor neurons are uniquely sensitive to perturbations in RNA processing pathways dependent on the interaction of specific RNAs with specific RNA-binding proteins, which presumably result in aberrant formation and function of ribonucleoprotein complexes. This review provides a summary of currently recognized RNA processing defects linked to human motor neuron diseases.


Asunto(s)
Enfermedad de la Neurona Motora/genética , Neuronas Motoras/fisiología , Mutación , Procesamiento Postranscripcional del ARN/genética , ARN/metabolismo , Humanos , Enfermedad de la Neurona Motora/metabolismo , Enfermedad de la Neurona Motora/fisiopatología , ARN/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo
13.
ACS Catal ; 10(21): 13075-13083, 2020 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-33791144

RESUMEN

A unified synthetic strategy to access tertiary four-membered carbo/heterocyclic boronic esters is reported. Use of a Cu(I) catalyst in combination with a modified dppbz ligand enables regioselective hydroboration of various trisubstituted benzylidenecyclobutanes and carbo/heterocyclic analogs. The reaction conditions are mild, and the method tolerates a wide range of medicinally relevant heteroarenes. The protocol can be conveniently conducted on gram-scale, and the tertiary boronic ester products undergo facile diversification into valuable targets. Reaction kinetics and computational studies indicate that the migratory insertion step is turnover-limiting and accelerated by electron-withdrawing groups on the dppbz ligand. Energy decomposition analysis (EDA) calculations reveal that electron-deficient P-aryl groups on the dppbz ligand enhance the T-shaped π/π interactions with the substrate and stabilize the migratory insertion transition state.

14.
J Comb Chem ; 11(5): 860-74, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19583220

RESUMEN

As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library of racemic resorcinol amides was prepared affording 131 purified compounds. After evaluation in a binding assay, followed by an AKT-Luminex cellular assay, three potent analogs had functional activity between 0.1 and 0.3 microM. Resolution by preparative chiral SFC chromatography led to (+)-15, (+)-16, and (+)-17 having functional IC(50) = 27, 43, and 190 nM, respectively. (+)-15 exhibited high clearance in human hepatocytes driven primarily by glucuronidation as confirmed by metabolite identification. A second 8 x 14 exploratory library was designed to investigate heterocyclic replacements of the resorcinol ring. The second library highlights the use of the (-)-sparteine-mediated enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine to prepare chiral 2-arylpyrrolidines in parallel.


Asunto(s)
Cromatografía en Gel/métodos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Glucurónidos/metabolismo , Proteínas HSP90 de Choque Térmico/química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Enlace de Hidrógeno , Farmacocinética , Conformación Proteica
15.
J Int Assoc Provid AIDS Care ; 18: 2325958219855377, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31213120

RESUMEN

OBJECTIVES: To evaluate the association between human immunodeficiency virus (HIV) patients and medical costs (inpatient, outpatient, pharmacy, total) using a national cohort of HIV-infected Veterans and non-HIV matched controls within the Veteran's Affairs (VA) Administration system. DESIGN: This study used claims (January 2000 to December 2016) extracted from the VA Informatics and Computing Infrastructure and VA Health Economics Resource Center. Cases included Veterans with an International Classification of Diseases, Ninth Revision/International Classification of Diseases, Tenth Revision for HIV with at least 1 prescription for a complete antiretroviral therapy regimen (January 2000 to September 2016). Two non-HIV controls were exact matched on race, sex, month, and year of birth. All patients were followed until the earliest of the following: last date of VA activity, death, or December 31, 2016. RESULTS: A total of 79 578 patients (26 526 HIV and 53 052 non-HIV) met all study criteria. The average age was 49.3 years, 38% were black, 32% were white, and 97% were male for both the HIV and control cohorts. Adjusted multivariable logistic regression models demonstrated that HIV was associated with higher odds of incurring a pharmacy cost (odds ratio = 2286.45, 95% confidence interval: 322.79-16 195.82), 4-fold, and 2-fold higher odds of incurring both outpatient and inpatient costs compared to the matched controls, respectively. In adjusted multivariable gamma generalized linear models, HIV-positive patients had an almost 4-fold, 17-fold, and almost 2-fold higher cost than matched controls in total, pharmacy, and outpatient costs, respectively. CONCLUSIONS: This study found an association between HIV-positive patients having higher odds of incurring a medical cost as well as higher medical costs compared to non-HIV controls.


Asunto(s)
Fármacos Anti-VIH/economía , Infecciones por VIH/economía , Pacientes Internos/estadística & datos numéricos , Pacientes Ambulatorios/estadística & datos numéricos , Honorarios por Prescripción de Medicamentos/estadística & datos numéricos , Adulto , Fármacos Anti-VIH/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Costos de la Atención en Salud/estadística & datos numéricos , Gastos en Salud/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , Estados Unidos , Veteranos/estadística & datos numéricos
16.
J Med Chem ; 61(3): 650-665, 2018 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-29211475

RESUMEN

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.


Asunto(s)
Diseño de Fármacos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Isoquinolinas/farmacología , Isoquinolinas/farmacocinética , Administración Oral , Disponibilidad Biológica , Línea Celular Tumoral , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/química , Modelos Moleculares , Conformación Molecular
17.
PLoS One ; 12(2): e0172011, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28196149

RESUMEN

Elucidating how life history traits vary geographically is important to understanding variation in population dynamics. Because many aspects of ectotherm life history are climate-dependent, geographic variation in climate is expected to have a large impact on population dynamics through effects on annual survival, body size, growth rate, age at first reproduction, size-fecundity relationship, and reproductive frequency. The Eastern Massasauga (Sistrurus catenatus) is a small, imperiled North American rattlesnake with a distribution centered on the Great Lakes region, where lake effects strongly influence local conditions. To address Eastern Massasauga life history data gaps, we compiled data from 47 study sites representing 38 counties across the range. We used multimodel inference and general linear models with geographic coordinates and annual climate normals as explanatory variables to clarify patterns of variation in life history traits. We found strong evidence for geographic variation in six of nine life history variables. Adult female snout-vent length and neonate mass increased with increasing mean annual precipitation. Litter size decreased with increasing mean temperature, and the size-fecundity relationship and growth prior to first hibernation both increased with increasing latitude. The proportion of gravid females also increased with increasing latitude, but this relationship may be the result of geographically varying detection bias. Our results provide insights into ectotherm life history variation and fill critical data gaps, which will inform Eastern Massasauga conservation efforts by improving biological realism for models of population viability and climate change.


Asunto(s)
Cambio Climático , Variación Genética , Modelos Biológicos , Viperidae/fisiología , Animales , Femenino , Great Lakes Region , Masculino
18.
Nat Commun ; 7: 11384, 2016 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-27122193

RESUMEN

Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.


Asunto(s)
Antineoplásicos/química , Inhibidores Enzimáticos/química , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Complejo Represivo Polycomb 2/química , Resistencia a Antineoplásicos , Proteína Potenciadora del Homólogo Zeste 2/química , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Modelos Moleculares , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo
19.
J Med Chem ; 59(18): 8306-25, 2016 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-27512831

RESUMEN

A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Piridonas/química , Piridonas/farmacología , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ciclización , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Lactamas/química , Lactamas/farmacología , Ratones , Ratones SCID , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Piridonas/uso terapéutico
20.
J Med Chem ; 59(5): 2005-24, 2016 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-26756222

RESUMEN

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.


Asunto(s)
Descubrimiento de Drogas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Proteínas Mutantes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Modelos Moleculares , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
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