Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1).
Org Biomol Chem
; 14(24): 5505-10, 2016 Jun 28.
Article
en En
| MEDLINE
| ID: mdl-26751150
ABSTRACT
Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D (1)H-(15)N HSQC NMR spectroscopy with (15)N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Quinolinas
/
Diseño de Fármacos
/
Proteína 1 de la Secuencia de Leucemia de Células Mieloides
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Org Biomol Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos