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

Sergio Valente (1) , Ilaria Lepore (2) , Carmela Dell'Aversana (2) , Maria Tardugno (1, 3) , Sabrina Castellano (3) , Gianluca Sbardella (3) , Stefano Tomassi (4) , Salvatore Di Maro (4) , Ettore Novellino (4) , Roberto Di Santo (1) , Roberta Costi (1) , Lucia Altucci (2) , Antonello Mai (1)

1 Department of Medicinal Chemistry and Technologies
2 Dipartimento di Patologia Generale
3 Dipartimento di Scienze Farmaceutiche e Biomediche
4 Department of Pharmacy Naples

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.

Domains: Life Sciences [q-bio]; Pharmaceutical sciences

Sergio Valente, Ilaria Lepore, Carmela Dell'Aversana, Maria Tardugno, Sabrina Castellano, et al.. Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells.. Biochimie, 2012, 94 (11), pp.2308-13. ⟨10.1016/j.biochi.2012.06.003⟩. ⟨pasteur-00968696⟩