Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.
ACS Med Chem Lett
; 13(10): 1591-1597, 2022 Oct 13.
Article
de En
| MEDLINE
| ID: mdl-36262388
ABSTRACT
Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (â¼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-µM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Langue:
En
Journal:
ACS Med Chem Lett
Année:
2022
Type de document:
Article
Pays d'affiliation:
Royaume-Uni