A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach.
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.
†Epigenetic Med Chem Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy.
Ciro
C
Milite
†Epigenetic Med Chem Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy.
Alessandra
A
Feoli
‡Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan.|§Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Kazuki
K
Sasaki
∥Dipartimento di Farmacia, Università di Napoli "Federico II" Via D. Montesano 49, I-80131 Naples, Italy.
Valeria
V
La Pietra
†Epigenetic Med Chem Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy.
Amodio Luca
AL
Balzano
∥Dipartimento di Farmacia, Università di Napoli "Federico II" Via D. Montesano 49, I-80131 Naples, Italy.
Luciana
L
Marinelli
⊥Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, P.le A. Moro 5, I-00185 Rome, Italy.
Antonello
A
Mai
∥Dipartimento di Farmacia, Università di Napoli "Federico II" Via D. Montesano 49, I-80131 Naples, Italy.
Ettore
E
Novellino
†Epigenetic Med Chem Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy.|#Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via Salvador Allende, I-84081 Baronissi, Salerno, Italy.
Sabrina
S
Castellano
†Epigenetic Med Chem Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy.
Alessandra
A
Tosco
†Epigenetic Med Chem Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Salerno, Italy.
Gianluca
G
Sbardella
D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006657:Histones; D050880:p300-CBP Transcription Factors; D008239:Lysine