Human p300 is a polyhedric transcriptional coactivator, playing a crucial role by acetylating histones on specific lysine residues. A great deal of evidences shows that p300 is involved in several diseases as leukemia, tumors and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale as to how its modulation could represent an amenable drug target. Several p300 inhibitors (HATi) have been described so far, but all suffer from low potency, lack of specificity or low cell-permeability, highlighting the need to find more effective inhibitors. Our cinnamoyl derivative, RC 56, was identified as active and selective p300 inhibitor, proving to be a good hit candidate to investigate the structure-activity relationship towards p300. Herein we describe the design, synthesis and biological evaluation of new HATi structurally related to our hit, investigating, moreover, the interactions between p300 and the best-emerged hits by means of induced fit docking and molecular dynamics simulations, gaining insight on the peculiar chemical features that influenced their activity toward the targeted enzyme.

Structure-activity relationships on cynnamoyl derivatives as inhibitors of p300 Histone acetyltransferase / Madia, VALENTINA NOEMI; Benedetti, Rosaria; Letizia Barreca, Maria; Ngo, Liza; Pescatori, Luca; Messore, Antonella; Pupo, Giovanni; Saccoliti, Francesco; Valente, Sergio; Mai, Antonello; Scipione, Luigi; George Zheng, Yujun; Tintori, Cristina; Botta, Maurizio; Cecchetti, Violetta; Altucci, Lucia; DI SANTO, Roberto; Costi, Roberta. - In: CHEMMEDCHEM. - ISSN 1860-7187. - STAMPA. - 12:(2017), pp. 1359-1368. [10.1002/cmdc.201700040]

Structure-activity relationships on cynnamoyl derivatives as inhibitors of p300 Histone acetyltransferase

Valentina Noemi Madia;Luca Pescatori;Antonella Messore;Giovanni Pupo;Francesco Saccoliti;Sergio Valente;Antonello Mai;Luigi Scipione;Roberto Di Santo;Roberta Costi
2017

Abstract

Human p300 is a polyhedric transcriptional coactivator, playing a crucial role by acetylating histones on specific lysine residues. A great deal of evidences shows that p300 is involved in several diseases as leukemia, tumors and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale as to how its modulation could represent an amenable drug target. Several p300 inhibitors (HATi) have been described so far, but all suffer from low potency, lack of specificity or low cell-permeability, highlighting the need to find more effective inhibitors. Our cinnamoyl derivative, RC 56, was identified as active and selective p300 inhibitor, proving to be a good hit candidate to investigate the structure-activity relationship towards p300. Herein we describe the design, synthesis and biological evaluation of new HATi structurally related to our hit, investigating, moreover, the interactions between p300 and the best-emerged hits by means of induced fit docking and molecular dynamics simulations, gaining insight on the peculiar chemical features that influenced their activity toward the targeted enzyme.
2017
cinnamoyl compounds; HAT; anticancer
01 Pubblicazione su rivista::01a Articolo in rivista
Structure-activity relationships on cynnamoyl derivatives as inhibitors of p300 Histone acetyltransferase / Madia, VALENTINA NOEMI; Benedetti, Rosaria; Letizia Barreca, Maria; Ngo, Liza; Pescatori, Luca; Messore, Antonella; Pupo, Giovanni; Saccoliti, Francesco; Valente, Sergio; Mai, Antonello; Scipione, Luigi; George Zheng, Yujun; Tintori, Cristina; Botta, Maurizio; Cecchetti, Violetta; Altucci, Lucia; DI SANTO, Roberto; Costi, Roberta. - In: CHEMMEDCHEM. - ISSN 1860-7187. - STAMPA. - 12:(2017), pp. 1359-1368. [10.1002/cmdc.201700040]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1192249
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