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-3-carbethoxyquinoline 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.
Identification of small molecules inhibitors of GCN5 histone acetyltransferase activity / Mai, Antonello; Rotili, Dante; Ornaghi, P; Tosi, F; Vicidomini, C; Sbardella, G; Nebbioso, A; Altucci, L; Filetici, P.. - In: ARKIVOC. - ISSN 1551-7004. - 8:(2006), pp. 24-37.
Identification of small molecules inhibitors of GCN5 histone acetyltransferase activity
MAI, Antonello;ROTILI, Dante;
2006
Abstract
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-3-carbethoxyquinoline 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.