title: Structure-Activity Relationships on Cinnamoyl Derivatives as Inhibitors of p300 Histone Acetyltransferase.
abstract: Human p300 is a polyhedric transcriptional coactivator that plays a crucial role in acetylating histones on specific lysine residues. A great deal of evidence shows that p300 is involved in several diseases, including leukemia, tumors, and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale to determine how its modulation could represent an amenable drug target. Several p300 inhibitors (i.e., histone acetyltransferase inhibitors, HATis) have been described so far, but they all suffer from low potency, lack of specificity, or low cell permeability, which thus highlights the need to find more effective inhibitors. Our cinnamoyl derivative, 2,6-bis(3-bromo-4-hydroxybenzylidene)cyclohexanone (RC56), was identified as an active and selective p300 inhibitor and was proven to be a good hit candidate to investigate the structure-activity relationship toward p300. Herein, we describe the design, synthesis, and biological evaluation of new HATis structurally related to our hit; moreover, we investigate the interactions between p300 and the best-emerged hits by means of induced-fit docking and molecular-dynamics simulations, which provided insight into the peculiar chemical features that influence their activity toward the targeted enzyme.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Valentina Noemi
authors.identifier: 0000-0002-5724-612X
authors.initials: VN
authors.lastname: Madia
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia generale, Università degli Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138, Napoli, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Benedetti
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti 48, 06123, Perugia, Italy.
authors.forename: Maria Letizia
authors.identifier: 0000-0003-3530-5042
authors.initials: ML
authors.lastname: Barreca
authors.affiliation: Department of Pharmaceutical and Biochemical Sciences, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Liza
authors.initials: L
authors.lastname: Ngo
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Luca
authors.identifier: 0000-0003-4734-7856
authors.initials: L
authors.lastname: Pescatori
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Antonella
authors.identifier: 0000-0003-0158-5816
authors.initials: A
authors.lastname: Messore
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Giovanni
authors.identifier: 0000-0002-6011-0223
authors.initials: G
authors.lastname: Pupo
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Francesco
authors.identifier: 0000-0002-2907-5503
authors.initials: F
authors.lastname: Saccoliti
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Sergio
authors.identifier: 0000-0002-2241-607X
authors.initials: S
authors.lastname: Valente
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Antonello
authors.identifier: 0000-0001-9176-2382
authors.initials: A
authors.lastname: Mai
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Luigi
authors.identifier: 0000-0002-2006-7005
authors.initials: L
authors.lastname: Scipione
authors.affiliation: Department of Pharmaceutical and Biochemical Sciences, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Yujun George
authors.identifier: 0000-0001-7116-3067
authors.initials: YG
authors.lastname: Zheng
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Cristina
authors.identifier: 0000-0002-6002-0332
authors.initials: C
authors.lastname: Tintori
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Maurizio
authors.identifier: 0000-0003-0456-6995
authors.initials: M
authors.lastname: Botta
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti 48, 06123, Perugia, Italy.
authors.forename: Violetta
authors.identifier: 0000-0001-8558-7004
authors.initials: V
authors.lastname: Cecchetti
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia generale, Università degli Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138, Napoli, Italy.|Istituto di Genetica e Biofisica, IGB "Adriano Buzzati Traverso", Via P. Castellino 111, 80131, Napoli, Italy.
authors.forename: Lucia
authors.identifier: 0000-0002-7312-5387
authors.initials: L
authors.lastname: Altucci
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Roberto
authors.identifier: 0000-0002-4279-7666
authors.initials: R
authors.lastname: Di Santo
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Roberta
authors.identifier: 0000-0002-1314-9029
authors.initials: R
authors.lastname: Costi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002934:Cinnamates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003512:Cyclohexanones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: C520348:2,6-bis(3-bromo-4-hydroxybenzylidene)cyclohexanone; D001597:Benzylidene Compounds; D002934:Cinnamates; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: antitumor agents; drug discovery; medicinal chemistry; structure-activity relationships; transferases