Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1).
J Med Chem
; 54(24): 8490-500, 2011 Dec 22.
Article
en En
| MEDLINE
| ID: mdl-22040023
ABSTRACT
Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piridinas
/
Pirroles
/
Proteínas Serina-Treonina Quinasas
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Año:
2011
Tipo del documento:
Article