Identification of small molecules inhibitors of GCN5 histone acetyltransferase activity
Antonello Mai, Dante Rotili, Prisca Ornaghi, Federica Tosi, Caterina Vicidomini, Gianluca Sbardella, Angela Nebbioso, Lucia Altucci, Patrizia Filetici · ARKIVOC · 2006
Starting from a yeast phenotypic screening performed on 21 chemically different substances we described the discovery of two small molecules as GCN5 inhibitors.The 2-methyl-3carbethoxyquinoline 9 and its 2-desmethyl analogue 18 were able to significantly reduce the yeast cell growth, thus miming the effect of GCN5 deletion mutant.Tested to evaluate their effect on GCN5-dependent transcription of the HIS3 gene, 9 and 18 showed high inhibitory activity of gene transcription, more evident in activated conditions.Compound 9 was also able to reduce the acetylation levels of H3 and, to a lesser extent, H4 in yeast at 0.6 mM.In human leukemia U937 cells, at 1 mM concentration 9 showed 27% apoptosis induction, while 18 had just a little effect in the same conditions.Further studies on 9 and 18 will be performed to deepen their effects on GCN5-related phenomena.