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1.
Chem Res Toxicol ; 20(12): 1752-9, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18001056

RESUMEN

We have recently reported on the development of a La assay to detect reactive molecules by nuclear magnetic resonance (ALARM NMR) to detect reactive false positive hits from high-throughput screening, in which we observed a surprisingly large number of compounds that can oxidize or form covalent adducts with protein thiols groups. In the vast majority of these cases, the covalent interactions are largely nonspecific (e.g., affect many protein targets) and therefore unsuitable for drug development. However, certain thiol-reactive species do appear to inhibit the target of interest in a specific manner. The question then arises as to the potential toxicology risks of developing a drug that can react with protein thiol groups. Here, we report on the evaluation of a large set of ALARM-reactive and -nonreactive compounds against a panel of additional proteins (aldehyde dehydrogenase, superoxide dismutase, and three cytochrome P450 enzymes). It was observed that ALARM-reactive compounds have significantly increased risks of interacting with one or more of these enzymes in vitro. Thus, ALARM NMR seems to be a sensitive tool to rapidly identify compounds with an enhanced risk of producing side effects in humans, including alcohol intolerance, the formation of reactive oxygen species, and drug-drug interactions. In conjunction with other toxicology assays, ALARM NMR should be a valuable tool for prioritizing compounds for lead optimization and animal testing.


Asunto(s)
Aldehído Deshidrogenasa/química , Autoantígenos/química , Inhibidores Enzimáticos del Citocromo P-450 , Preparaciones Farmacéuticas , Ribonucleoproteínas/química , Compuestos de Sulfhidrilo/química , Superóxido Dismutasa/química , Aldehído Deshidrogenasa/metabolismo , Diseño de Fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Estructura Molecular , Preparaciones Farmacéuticas/análisis , Unión Proteica , Compuestos de Sulfhidrilo/metabolismo , Superóxido Dismutasa/metabolismo , Antígeno SS-B
2.
Chem Biol Drug Des ; 70(1): 1-12, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17630989

RESUMEN

The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.


Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Fragmentos de Péptidos , Aminopiridinas/química , Aminopiridinas/metabolismo , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Conformación Proteica
3.
Chem Biol Drug Des ; 69(6): 395-404, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17581233

RESUMEN

As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to HI0065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gene products that are not present in eukaryotic cells can identify novel antibacterial agents.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Química Farmacéutica/métodos , Haemophilus influenzae/metabolismo , Secuencia de Aminoácidos , Animales , Linfocitos B/metabolismo , Diseño de Fármacos , Genoma Bacteriano , Genómica , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Datos de Secuencia Molecular , Unión Proteica , Relación Estructura-Actividad
4.
J Med Chem ; 49(12): 3563-80, 2006 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-16759099

RESUMEN

The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.


Asunto(s)
Aminopiridinas/síntesis química , Proteína Quinasa 8 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 9 Activada por Mitógenos/antagonistas & inhibidores , Aminopiridinas/química , Aminopiridinas/farmacología , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Semivida , Humanos , Proteína Quinasa 10 Activada por Mitógenos/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/química , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Modelos Moleculares , Fosforilación , Conformación Proteica , Ratas , Ratas Sprague-Dawley
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