当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach.

A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach.

Abstract：

:Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular pruning approach to the hardly optimizable and not very cell-permeable garcinol core structure, we prepared many analogues that were screened for their inhibitory effects using biochemical and biophysical (SPR) assays. Further optimization led to the discovery of the benzylidenebarbituric acid derivative 7h (EML425) as a potent and selective reversible inhibitor of CBP/p300, noncompetitive versus both acetyl-CoA and a histone H3 peptide, and endowed with good cell permeability. Furthermore, in human leukemia U937 cells, it induced a marked and time-dependent reduction in the acetylation of lysine H4K5 and H3K9, a marked arrest in the G0/G1 phase and a significant increase in the hypodiploid nuclei percentage.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Milite C,Feoli A,Sasaki K,La Pietra V,Balzano AL,Marinelli L,Mai A,Novellino E,Castellano S,Tosco A,Sbardella G

doi

10.1021/jm5019687

subject

Has Abstract

pub_date

2015-03-26 00:00:00

pages

2779-98

issue

6

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章

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