Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells

• Published in: Biochimie Vol. 94; no. 11; pp. 2308 - 2313
• Main Authors: Valente, Sergio, Lepore, Ilaria, Dell'Aversana, Carmela, Tardugno, Maria, Castellano, Sabrina, Sbardella, Gianluca, Tomassi, Stefano, Di Maro, Salvatore, Novellino, Ettore, Di Santo, Roberto, Costi, Roberta, Altucci, Lucia, Mai, Antonello
• Format: Journal Article
• Language: English
• Published: France Elsevier B.V 01.11.2012; Elsevier
• Subjects: Bis(bromo- and dibromo-phenol) compounds; Cell Cycle; Cell Cycle - drug effects; Cell Death; Cell Death - drug effects; Cell Differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Epi-drugs; Epigenetics; Granulocytes; Granulocytes - cytology; Granulocytes - drug effects; Histocompatibility Antigens; Histocompatibility Antigens - metabolism; Histone methylation; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - metabolism; Histones; Histones - metabolism; Humans; Leukemia; Leukemia - pathology; Life Sciences; Methylation; Methylation - drug effects; Pharmaceutical sciences; Polycomb Repressive Complex 2; Polycomb Repressive Complex 2 - antagonists & inhibitors; Polycomb Repressive Complex 2 - metabolism; Substrate Specificity; Epi-drugs; Epigenetics; Bis(bromo- and dibromo-phenol) compounds; Histone methylation; Leukemia
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2012.06.003

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 (EC50 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. [Display omitted] ► Chemical manipulations made on broad HMT inhibitors afforded compounds more selectively. ► Bis(dibromo) analogs 5 and 10 showed selective activity against PR-SET7. ► Bis(monobromo) analogs 4 and 9 showed dual PR-SET7 and EZH2 inhibition. ► Bis(monobromo) analog 4 induced massive cell death in U937 cells.