title: Small-molecule inhibitors of histone acetyltransferase activity: identification and biological properties.
abstract: 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 cell nuclear extracts to evaluate their histone acetyltransferase (HAT) inhibitory action, both compounds were able to reduce the enzyme activity when used at 500 microM. 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 and 25 microM, thereby 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 the extent of the acetylation levels of histone H3 (9) and alpha-tubulin (9 and 18). In the same assay, 22 at lower concentration (100 microM) showed the same hypoacetylating effects with both histone and non-histone substrates.
authors.affiliation: Dipartimento di Studi Farmaceutici, Istituto Pasteur--Fondazione Cenci Bolognetti, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. antonello.mai@uniroma1.it
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Domenico
authors.initials: D
authors.lastname: Tarantino
authors.forename: Prisca
authors.initials: P
authors.lastname: Ornaghi
authors.forename: Federica
authors.initials: F
authors.lastname: Tosi
authors.forename: Caterina
authors.initials: C
authors.lastname: Vicidomini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Marco
authors.initials: M
authors.lastname: Miceli
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Patrizia
authors.initials: P
authors.lastname: Filetici
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006801:Humans; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D020298:U937 Cells; D000099224:p300-CBP-Associated Factor
chemical_list: D000970:Antineoplastic Agents; D051548:Histone Acetyltransferases; D006657:Histones; D011804:Quinolines; D029701:Saccharomyces cerevisiae Proteins; D014404:Tubulin; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor