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Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1.

Abstract：

:Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Ghazy E,Zeyen P,Herp D,Hügle M,Schmidtkunz K,Erdmann F,Robaa D,Schmidt M,Morales ER,Romier C,Günther S,Jung M,Sippl W

doi

10.1016/j.ejmech.2020.112338

subject

Has Abstract

pub_date

2020-08-15 00:00:00

pages

112338

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30307-X

journal_volume

200

pub_type

杂志文章

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