Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Nature ; 550(7677): 481-486, 2017 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-29045389

RESUMEN

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.


Asunto(s)
Piperidinas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Peptidasa Específica de Ubiquitina 7/antagonistas & inhibidores , Animales , Apoenzimas/antagonistas & inhibidores , Apoenzimas/química , Apoenzimas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , Humanos , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Piperidinas/síntesis química , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirazoles/síntesis química , Pirimidinas/síntesis química , Especificidad por Sustrato , Transcripción Genética/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Peptidasa Específica de Ubiquitina 7/química , Peptidasa Específica de Ubiquitina 7/metabolismo , Ubiquitinación/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
ACS Med Chem Lett ; 8(8): 847-852, 2017 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-28835800

RESUMEN

A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound FT001, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).

3.
Chem Commun (Camb) ; 46(1): 70-2, 2010 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-20024296

RESUMEN

Two strategies toward the total synthesis of maoecrystal V (1) culminating in the construction of core structures 2 and 3 are described.


Asunto(s)
Diterpenos/síntesis química , Línea Celular Tumoral , Cristalografía por Rayos X , Diterpenos/química , Diterpenos/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Isodon/química , Conformación Molecular , Plantas Medicinales/química
6.
J Org Chem ; 68(7): 2844-52, 2003 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-12662061

RESUMEN

A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...