RESUMEN
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.
Asunto(s)
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
Over the last decade, a number of computational methods have been developed, which attempt to evaluate the thermodynamic properties of individual water molecules at the solute-solvent interface, in order to assess contributions to protein-ligand binding. In some cases, these tools tell us what we already know, e.g. that hydrophobic pockets prefer lipophilic substituents, and in other cases the methods only seem to add clarity when retrospectively applied. Hence we have grappled with how to utilize such approaches to understand non-intuitive results and to generate chemistry ideas that otherwise would not have been developed. Here we provide our perspective on these methods and describe how results have been interpreted and applied. We include examples from GSK and elsewhere that highlight how water methods have been (1) utilized retrospectively to explain non-intuitive structure- activity relationships and (2) applied prospectively for chemistry design. Finally, we discuss where this field of study could lead to maximal impact in drug discovery research.
Asunto(s)
Diseño de Fármacos , Agua/química , Ligandos , Estructura Molecular , Proteínas/química , TermodinámicaRESUMEN
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.
RESUMEN
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.
RESUMEN
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
Asunto(s)
Antineoplásicos/química , Diaminas/química , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirimidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular , Diaminas/síntesis química , Diaminas/farmacología , Descubrimiento de Drogas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Morfolinas/síntesis química , Morfolinas/farmacología , Complejos Multiproteicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Proteínas , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.
Asunto(s)
Antineoplásicos/química , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirimidinas/química , Triazinas/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Morfolinas/síntesis química , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Triazinas/síntesis química , Triazinas/farmacologíaRESUMEN
We have previously described poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a substituted benzyl-phthalazinone scaffold. As an alternative chemical template, a novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Química Farmacéutica , Diseño de Fármacos , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Estructura Molecular , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Age effects on sexual attitudes were examined using the Hendrick and Hendrick (1987a) Sexual Attitude Scale. The study was cross-sectional, including people from various age groups, from young adults to older adults. The religious beliefs variable, which covaries substantially both with age and sexual attitudes, was controlled. Three main questions guided the study: (a) Is the four-factor structure (Permissiveness, Instrumentality, Communion, and Sexual Practices) previously identified in a sample of young students able to accurately account for data gathered over a full range of adult ages, (b) are older adults much less permissive and less instrumentalist than young people, and (c) to what extent are believers less permissive and instrumentalist than young people when age is taken into account? Factor analyses showed that at least five correlated factors were needed to account for the data; the fourth factor, Sexual Practices, divided itself into two distinct factors: Pleasure and Responsibility. Older adults and believers were shown to be less permissive than young people and nonbelievers, and this result held regardless of the participants educational level. As regards to instrumentality, however, the pattern of differences was extremely complex.