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DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULE MODULATORS OF PROTEIN LYSINE METHYLTRANSFERASES (KMTS)

- The first objective of this project will be the design and the synthesis of a small library of putative modulators of G9a. At first we will use 6,7-dimethoxyquinazoline analogues (potent and selective substrate competitive inhibitors of G9a) as lead compounds. These inhibitors, in fact, are generally excellent tools in vitro but are inadequate for animal studies due to their poor in vivo pharmacokinetic properties.- The second objective will be the design and the synthesis of a small library of putative modulators of Pr-Set7. To this aim, we will consider the optimization of dye-like scaffolds previously identified by our group.- The third part of the project will be aimed at evaluating the biological activity of novel compounds. All the derivatives will be preliminarily screened using AlphaScreen® technology. The most interesting derivatives will be further investigated to validate their capability to inhibit target enzymes in cellular assays.- The fourth part of the project will be the hit-to-lead optimization of most interesting active compounds. Basing on the preliminary structure-activity relationships obtained, the optimization will be driven by classical medicinal chemistry approaches, such as bioisosterism, frozen analog approach, insertion of privileged structures, appendage diversity etc., approaches already successfully used by our research group in the development of modulators of epigenetic enzymes.Gli 2n + 1 lavori in considerazione: IN MAIUSCOLO gli autori partecipanti al progetto, in grassetto la proprietà scientificaIF 20161) Matteo Vecellio, Francesco Spallotta, Simona Nanni, Claudia Colussi, Chiara Cencioni, Anja Derlet, Beatrice Bassetti, Manuela Tilenni, Maria Cristina Carena, Antonella Farsetti, GIANLUCA SBARDELLA, SABRINA CASTELLANO, Antonello Mai, Fabio Martelli, Giulio Pompilio, Maurizio C. Capogrossi, Alessandra Rossini, Stefanie Dimmeler, Andreas M. Zeiher, Carlo GaetanoThe Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients, Diabetes, 2014, 63, 2132–2147. DOI: 10.2337/db13-0731IF: 8,684; FC: 1; Tot: 8,6842) Ciro Milite, Alessandra Feoli, Kazuki Sasaki, Valeria La Pietra, Amodio Luca Balzano, Luciana Marinelli, Antonello Mai, Ettore Novellino, SABRINA CASTELLANO*, Alessandra Tosco, and GIANLUCA SBARDELLA*A novel cell-permeable, selective and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach.J. Med. Chem. 2015, 58, 2779–2798. DOI: 10.1021/jm5019687IF: 6,259; FC:1,5; Tot: 9,38853) SABRINA CASTELLANO, Sabrina Taliani, Monica Viviano, Ciro Milite, Eleonora Da Pozzo, Barbara Costa, Elisabetta Barresi, Agostino Bruno, Sandro Cosconati, Luciana Marinelli, Giovanni Greco, Ettore Novellino, GIANLUCA SBARDELLA, Federico Da Settimo, Claudia MartiniStructure–Activity Relationship Refinement and Further Assessment of 4-phenylquinazoline-2-carboxamide Translocator Protein (TSPO) Ligands as Antiproliferative Agents in Human Glioblastoma Tumors.J. Med. Chem. 2014, 57, 2413–2428. DOI: 10.1021/jm401721hIF: 6,259; FC:1,5; Tot: 9,38854) Maria G. Chini, Nicola Malafronte, Maria C. Vaccaro, Maria J. Gualtieri, Antonio Vassallo, Michele Vasaturo, SABRINA CASTELLANO, Ciro Milite, Antonietta Leone, Giuseppe Bifulco, Nunziatina De Tommasi, Fabrizio Dal PiazIdentification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary ApproachChem. Eur. J. 2016, 22, 13236 –13250. DOI: 10.1002/chem.201602242IF: 5,317; FC:1,0; Tot: 5,3175) SABRINA CASTELLANO, Ciro Milite, Alessandra Feoli, Monica Viviano, Antonello Mai, Ettore Novellino, Alessandra Tosco, GIANLUCA SBARDELLA*Identification of Structural Features of 2-Alkylidene-1,3-Dicarbonyl Derivatives that Induce Inhibition and/orActivation of Histone Acetyltransferases KAT3B/p300 and KAT2B/PCAFChemMedChem 2015, 10, 144–157. DOI: 10.1002/c mdc.201402371IF: 3,225; FC:1,5; Tot: 4,8375