Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.
ACS Med Chem Lett
; 9(1): 28-33, 2018 Jan 11.
Article
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| MEDLINE
| ID: mdl-29348807
ABSTRACT
p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos