Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells.
Chemical manipulations undertaken on some bis(bromo- and dibromo-phenol) compounds previously reported by us as wide-spectrum epigenetic inhibitors let us to identify bis (bromo- and dibromo-methoxyphenyl) derivatives highly selective for PR-SET7 and EZH2 (compounds 4, 5, 9, and 10). Western blot analyses were carried out in U937 cells to determine the effects of such compounds on the methyl marks related to the tested enzymes (H3K4me1, H3K9me2, H4H20me1, and H3K27me3). The 1,5-bis(3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one 4 (EC(50) vs EZH2 = 74.9 μM), tested in U937 cells at 50 μM, induced massive cell death and 28% of granulocytic differentiation, highlighting the potential use of EZH2 inhibitors in cancer.
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P.le A. Moro 5, 00185 Roma, Italy.
Sergio
S
Valente
Ilaria
I
Lepore
Carmela
C
Dell'Aversana
Maria
M
Tardugno
Sabrina
S
Castellano
Gianluca
G
Sbardella
Stefano
S
Tomassi
Salvatore
S
Di Maro
Ettore
E
Novellino
Roberto
R
Di Santo
Roberta
R
Costi
Lucia
L
Altucci
Antonello
A
Mai
D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008745:Methylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D006649:Histocompatibility Antigens; D006657:Histones; D000076983:Histone Methyltransferases; C445405:EHMT2 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D063151:Polycomb Repressive Complex 2