title: Identification of structural features of 2-alkylidene-1,3-dicarbonyl derivatives that induce inhibition and/or activation of histone acetyltransferases KAT3B/p300 and KAT2B/PCAF.
abstract: Dysregulation of the activity of lysine acetyltransferases (KATs) is related to a variety of diseases and/or pathological cellular states; however, their role remains unclear. Therefore, the development of selective modulators of these enzymes is of paramount importance, because these molecules could be invaluable tools for assessing the importance of KATs in several pathologies. We recently found that diethyl pentadecylidenemalonate (SPV106) possesses a previously unobserved inhibitor/activator activity profile against protein acetyltransferases. Herein, we report that manipulation of the carbonyl functions of a series of analogues of SPV106 yielded different activity profiles against KAT2B and KAT3B (pure KAT2B activator, pan-inhibitor, or mixed KAT2B activator/KAT3B inhibitor). Among the novel compounds, a few derivatives may be useful chemical tools for studying the mechanism of lysine acetylation and its implications in physiological and/or pathological processes.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano (SA) (Italy).
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.forename: Ciro
authors.initials: C
authors.lastname: Milite
authors.forename: Alessandra
authors.initials: A
authors.lastname: Feoli
authors.forename: Monica
authors.initials: M
authors.lastname: Viviano
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tosco
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D010802:Phylogeny; D011485:Protein Binding; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D050880:p300-CBP Transcription Factors / Q000819:agonists* / Q000145:classification / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D050881:E1A-Associated p300 Protein; D004791:Enzyme Inhibitors; D006657:Histones; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: PCAF activators; epigenetics; lysine acetyltransferases; structure-activity relationships; surface plasmon resonance