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

Journal of Medicinal Chemistry
Ciro MiliteGianluca Sbardella

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.

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Citations

Jan 26, 2016·Pharmacology & Therapeutics·Stephanie KaypeeTapas K Kundu
Dec 25, 2015·Journal of Medicinal Chemistry·Roman P SimonManfred Jung
Oct 7, 2015·Frontiers in Immunology·Francesco CascielloJason S Lee
May 28, 2016·Clinical Epigenetics·Hannah Wapenaar, Frank J Dekker
Apr 21, 2018·Future Medicinal Chemistry·Francesco FiorentinoDante Rotili
Aug 7, 2019·Chemistry & Biodiversity·Rainer Schobert, Bernhard Biersack
Sep 10, 2020·Frontiers in Pharmacology·Francesco FiorentinoDante Rotili
Mar 20, 2019·Scientific Reports·Justyna McIntyreEwa Sledziewska-Gojska
Oct 13, 2020·European Journal of Medicinal Chemistry·Zhang-Xu HeWen Zhao
Nov 21, 2020·Polymers·Eva Marina Briz-LópezÁngel Marcos-Fernández
Apr 24, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Bing GaoJianping Guo
Mar 12, 2021·Seminars in Cancer Biology·Fabin Dang, Wenyi Wei
Jul 31, 2021·Microscopy·Yuko SatoHiroshi Kimura
May 19, 2018·Journal of Medicinal Chemistry·Francesco MerlinoLuciana Marinelli

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