2. Academic Validation
  3. 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

  • J Med Chem. 2015 Mar 26;58(6):2779-98. doi: 10.1021/jm5019687.
Ciro Milite 1,  Alessandra Feoli 1,  Kazuki Sasaki 2 3,  Valeria La Pietra 4,  Amodio Luca Balzano 1,  Luciana Marinelli 4,  Antonello Mai 5,  Ettore Novellino 4,  Sabrina Castellano 1 6,  Alessandra Tosco 1,  Gianluca Sbardella 1
Affiliations

Affiliations

  • 1 †Epigenetic Med Chem Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy.
  • 2 ‡Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan.
  • 3 §Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
  • 4 ∥Dipartimento di Farmacia, Università di Napoli "Federico II" Via D. Montesano 49, I-80131 Naples, Italy.
  • 5 ⊥Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, P.le A. Moro 5, I-00185 Rome, Italy.
  • 6 #Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via Salvador Allende, I-84081 Baronissi, Salerno, Italy.
PMID: 25730130 DOI: 10.1021/jm5019687
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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