LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.
Angew Chem Int Ed Engl
; 54(21): 6217-21, 2015 May 18.
Article
en En
| MEDLINE
| ID: mdl-25864491
ABSTRACT
The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis:
Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones inâ vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Proteínas Cromosómicas no Histona
/
Descubrimiento de Drogas
/
Lactamas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2015
Tipo del documento:
Article