RESUMEN
Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.
Asunto(s)
Antineoplásicos/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/uso terapéutico , Piridonas/uso terapéutico , Pirimidinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Dominio Catalítico , Línea Celular Tumoral , Diseño de Fármacos , Factor 4E Eucariótico de Iniciación/química , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Estructura Molecular , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Piridonas/síntesis química , Piridonas/química , Piridonas/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Serina/química , Transducción de Señal/efectos de los fármacos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We present Illuminator, a user-friendly web front end to computational models such as docking and 3D shape similarity calculations. Illuminator was specifically created to allow non-experts to design and submit molecules to computational chemistry programs. As such it provides a simple user interface allowing users to submit jobs starting from a 2D structure. The models provided are pre-optimized by computational chemists for each specific target. We provide an example of how Illuminator was used to prioritize the design of molecular substituents in the Anadys HCV Polymerase (NS5B) project. With 7500 submitted jobs in 1.5 years, Illuminator has allowed project teams at Anadys to accelerate the optimization of novel leads. It has also improved communication between project members and increased demand for computational drug discovery tools.
Asunto(s)
Química Farmacéutica/métodos , Técnicas Químicas Combinatorias , Biología Computacional , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Modelos Moleculares , Conformación Molecular , Programas InformáticosRESUMEN
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
Asunto(s)
Disponibilidad Biológica , Diseño de Fármacos , Relación Estructura-Actividad , Antivirales/farmacocinética , Química Farmacéutica , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C , Estructura Molecular , ARN Polimerasa Dependiente del ARN , Proteínas no Estructurales Virales/antagonistas & inhibidoresRESUMEN
The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.
Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Piridonas/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Animales , Antivirales/síntesis química , Antivirales/farmacología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Piridonas/síntesis química , Piridonas/farmacología , ARN Polimerasa Dependiente del ARN/metabolismo , Relación Estructura-ActividadRESUMEN
Structural studies of antibiotics not only provide a shortcut to medicine allowing for rational structure-based drug design, but may also capture snapshots of dynamic intermediates that become 'frozen' after inhibitor binding. Myxopyronin inhibits bacterial RNA polymerase (RNAP) by an unknown mechanism. Here we report the structure of dMyx--a desmethyl derivative of myxopyronin B--complexed with a Thermus thermophilus RNAP holoenzyme. The antibiotic binds to a pocket deep inside the RNAP clamp head domain, which interacts with the DNA template in the transcription bubble. Notably, binding of dMyx stabilizes refolding of the beta'-subunit switch-2 segment, resulting in a configuration that might indirectly compromise binding to, or directly clash with, the melted template DNA strand. Consistently, footprinting data show that the antibiotic binding does not prevent nucleation of the promoter DNA melting but instead blocks its propagation towards the active site. Myxopyronins are thus, to our knowledge, a first structurally characterized class of antibiotics that target formation of the pre-catalytic transcription initiation complex-the decisive step in gene expression control. Notably, mutations designed in switch-2 mimic the dMyx effects on promoter complexes in the absence of antibiotic. Overall, our results indicate a plausible mechanism of the dMyx action and a stepwise pathway of open complex formation in which core enzyme mediates the final stage of DNA melting near the transcription start site, and that switch-2 might act as a molecular checkpoint for DNA loading in response to regulatory signals or antibiotics. The universally conserved switch-2 may have the same role in all multisubunit RNAPs.
Asunto(s)
ARN Polimerasas Dirigidas por ADN/química , ARN Polimerasas Dirigidas por ADN/metabolismo , Pliegue de Proteína , Thermus thermophilus/enzimología , Transcripción Genética , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Apoproteínas/química , Sitios de Unión , Cristalografía por Rayos X , ARN Polimerasas Dirigidas por ADN/genética , Holoenzimas/química , Holoenzimas/metabolismo , Lactonas/química , Lactonas/metabolismo , Lactonas/farmacología , Modelos Biológicos , Modelos Moleculares , Conformación Molecular/efectos de los fármacos , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Estructura Terciaria de Proteína , Thermus thermophilus/genética , Sitio de Iniciación de la Transcripción , Transcripción Genética/efectos de los fármacosRESUMEN
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).
Asunto(s)
ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridonas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Piridonas/administración & dosificación , Piridonas/química , Piridonas/farmacocinética , Relación Estructura-ActividadRESUMEN
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
Asunto(s)
Antivirales/síntesis química , Química Farmacéutica/métodos , Óxidos S-Cíclicos/síntesis química , Piridazinas/química , Piridazinas/síntesis química , Tiadiazinas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/química , Antivirales/farmacología , Células CACO-2 , Cristalografía por Rayos X/métodos , Óxidos S-Cíclicos/farmacología , ARN Polimerasas Dirigidas por ADN/química , Diseño de Fármacos , Genotipo , Humanos , Concentración 50 Inhibidora , Microsomas/metabolismo , Modelos Químicos , Conformación Molecular , Piridazinas/farmacología , Relación Estructura-Actividad , Tiadiazinas/farmacologíaRESUMEN
Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Piridazinas/síntesis química , Piridazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Estructura Molecular , Piridazinas/química , Relación Estructura-ActividadRESUMEN
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).
Asunto(s)
Química Farmacéutica/métodos , Hepacivirus/enzimología , Microsomas Hepáticos/enzimología , Piridazinas/síntesis química , Piridazinas/farmacología , Tiazinas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/química , Células CACO-2 , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Hepacivirus/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Piridazinas/química , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacología , Factores de TiempoRESUMEN
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Tiazoles/síntesis química , Tiofenos/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Genotipo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , ARN Viral/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiofenos/farmacocinéticaRESUMEN
Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).
Asunto(s)
Antivirales/farmacología , Piridazinas/farmacología , Pirroles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Sitios de Unión/efectos de los fármacos , Línea Celular , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Proteínas no Estructurales Virales/químicaRESUMEN
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Hepacivirus/efectos de los fármacos , Piridazinas/síntesis química , Piridazinas/farmacocinética , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/sangre , Antivirales/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Piridazinas/sangre , Piridazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Hepacivirus/enzimología , Piridazinas/síntesis química , Piridazinas/farmacocinética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Haplorrinos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Piridazinas/química , Relación Estructura-ActividadRESUMEN
Translation inhibitors of the 3,5-diamino-piperidine series act as aminoglycoside mimetics that inhibit bacterial growth. Here we show antibacterial SAR in the presence and absence of serum with a particular focus toward Pseudomonas aeruginosa.
Asunto(s)
Aminoglicósidos/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Diaminas/síntesis química , Diaminas/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Animales , Antibacterianos/sangre , Técnicas Químicas Combinatorias , Diaminas/sangre , Escherichia coli/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperidinas/sangre , Relación Estructura-ActividadRESUMEN
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The synthesis, structure-activity relationships (SAR), metabolic stability, and structure-based design approach for this new class of compounds are discussed.
Asunto(s)
Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Piridazinas/química , Piridazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Benzotiadiazinas/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Estabilidad de Medicamentos , Inhibidores Enzimáticos/metabolismo , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piridazinas/metabolismo , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure-activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Piridazinas/química , Piridazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Cristalografía por Rayos X , Diseño de Fármacos , Estabilidad de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piridazinas/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Tiadiazinas/síntesis química , Tiadiazinas/química , Tiadiazinas/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.
Asunto(s)
Diseño de Fármacos , Guanosina/análogos & derivados , Profármacos/administración & dosificación , Profármacos/síntesis química , Pirimidinonas/administración & dosificación , Pirimidinonas/síntesis química , Receptor Toll-Like 7/agonistas , Administración Oral , Antivirales/farmacología , Guanosina/farmacología , Humanos , Profármacos/química , Profármacos/farmacocinética , Pirimidinonas/química , Pirimidinonas/farmacocinéticaRESUMEN
W/C emulsions were stabilized using hydrophobic silica particles adsorbed at the interface, resulting in average droplet diameters as low as 7.5 microm. A porous cross-linked shell was formed about a hydrophilic (colloidal and fumed) silica core with a trifunctional silylating agent, (heptadecafluoro-1,1,2,2-tetrahydrodecyl)triethyoxysilane, to render the particles CO(2)-philic. The stability of emulsions comprising equal weights of CO(2) and water was assessed with visual observations of settling fronts and the degree of emulsion coalescence, and the average drop size was measured by optical microscopy. The effect of CO(2) density on both emulsion stability and droplet size was determined quantitatively. The major destabilizing mechanism of the emulsions was settling, whereas Ostwald ripening and coalescence were not visible at any density, even over 7 days. Flocculation of the settling droplets did not occur, although gelation of the emulsions through particle interactions resulted after longer periods of time. CO(2)-philic particles offer a new route to highly stable W/C emulsions, with particle energies of attachment on the order of 10(6)kT, even at CO(2) densities as low as 0.78 g ml(-1). At these low densities, surfactants rarely stabilize emulsions as the result of poor surfactant tail solvation.
Asunto(s)
Dióxido de Carbono/química , Dióxido de Silicio/química , Agua/química , Emulsiones , Interacciones Hidrofóbicas e Hidrofílicas , Microscopía/métodos , Óptica y Fotónica , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Based upon observations from our initial findings, additional myxopyronin B analogs have been prepared and tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against Escherichia coli and Staphylococcus aureus.
Asunto(s)
ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Lactonas/química , Lactonas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , ARN Polimerasas Dirigidas por ADN/metabolismo , Inhibidores Enzimáticos/química , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Concentración 50 Inhibidora , Lactonas/síntesis química , Metilación , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimologíaRESUMEN
Our previous photophysical study of water soluble perylene diimides (WS-PDIs) has suggested that WS-PDIs are present in aqueous solution in partially aggregated form (Tang, T. J.; Qu, J. Q.; Müllen, K.; Webber, S. E. Langmuir 2006, 22, 7610-7616) In this article we present a study of the effect of surfactants (dodecyltrimethylammonium chloride (DTAC), sodium dodecyl sulfate (SDS)) on the photophysics of WS-PDIs. Adding surfactant to WS-PDI solutions is accompanied by their increased fluorescence quantum yield and lifetime and a more structured absorption spectra. We are able to demonstrate that above the surfactant critical micelle concentration (cmc) the WS-PDI moieties are molecularly dispersed and isolated from each other. Our findings are consistent with the existence of weakly interacting aggregates of WS-PDIs in pure water, which can be broken up by surfactants even below the cmc, although we cannot rule out that the observed photophysical changes arise from modifying the local environment of molecularly solubilized WS-PDIs (e.g., local polarity or modification of the molecular planarity).