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Structure–Activity Relationships on Cinnamoyl Derivatives as Inhibitors of p300 Histone Acetyltransferase
Author(s) -
Madia Valentioemi,
Benedetti Rosaria,
Barreca Maria Letizia,
Ngo Liza,
Pescatori Luca,
Messore Antonella,
Pupo Giovanni,
Saccoliti Francesco,
Valente Sergio,
Mai Antonello,
Scipione Luigi,
Zheng Yujun George,
Tintori Cristina,
Botta Maurizio,
Cecchetti Violetta,
Altucci Lucia,
Di Santo Roberto,
Costi Roberta
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700040
Subject(s) - histone acetyltransferase , acetyltransferase , chemistry , acetylation , p300 cbp transcription factors , histone , histone deacetylase , pharmacology , histone acetyltransferases , stereochemistry , biochemistry , medicine , gene
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.