Small-Molecule Inhibitors of Histone Acetyltransferase Activity: Identification and Biological Properties

Starting from a yeast phenotypic screening performed on 21 compounds we described the identification of two small molecules (9 and 18) able to significantly reduce the S. cerevisiae cell growth thus miming the effect of GCN5 deletion mutant. Tested on a GCN5-dependent gene transcription assay, compounds 9 and 18 gave a high reduction of the reporter activity. In S. cerevisiae histone H3 terminal tails assay, the H3 acetylation levels were highly reduced by treatment with 0.6-1 mM 9, while 18 was effective only at 1.5 mM. In human leukemia U937 cell line, at 1 mM 9 and 18 showed effects on cell cycle (arrest in G1 phase, 9), apoptosis (9), and granulocytic differentiation (18). When tested on U937 cells nuclear extracts to evaluate their HAT inhibitory action, both compounds were able to reduce the enzyme activity at 500 µM. Another quinoline, compound 22, was synthesized with the aim to improve the activity observed with 9 and 18. Tested in the HAT assay, 22 was able to reduce the HAT catalytic action at 50 as well as 25 µM, it being comparable to anacardic acid, curcumin, and MB-3 used as references. Finally, in U937 cells compounds 9 and 18 used at 2.5 mM were able to reduce to somewhat extent the acetylation levels of histone H3 (9) and alpha-tubulin (9 and 18). In the same assay, 22 at lower concentration (100 µM) showed the same hypoacetylating effects with both histone and non-histone substrates