title: Development of 1,2,4-Oxadiazoles as Potent and Selective Inhibitors of the Human Deacetylase Sirtuin 2: Structure-Activity Relationship, X-ray Crystal Structure, and Anticancer Activity.
abstract: Sirt2 is a target for the treatment of neurological, metabolic, and age-related diseases including cancer. Here we report a series of Sirt2 inhibitors based on the 1,2,4-oxadiazole scaffold. These compounds are potent Sirt2 inhibitors active at single-digit μM level by using the Sirt2 substrate α-tubulin-acetylLys40 peptide and inactive up to 100 μM against Sirt1, -3, and -5 (deacetylase and desuccinylase activities). Their mechanism of inhibition is uncompetitive toward both the peptide substrate and NAD+, and the crystal structure of a 1,2,4-oxadiazole analog in complex with Sirt2 and ADP-ribose reveals its orientation in a still unexplored subcavity useful for further inhibitor development. Tested in leukemia cell lines, 35 and 39 induced apoptosis and/or showed antiproliferative effects at 10 or 25 μM after 48 h. Western blot analyses confirmed the involvement of Sirt2 inhibition for their effects in NB4 and in U937 cells. Our results provide novel Sirt2 inhibitors with a compact scaffold and structural insights for further inhibitor improvement.
authors.affiliation: Department of Biochemistry and Research Center for Bio-Macromolecules, University of Bayreuth , 95440 Bayreuth, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moniot
authors.affiliation: Department of Drug Chemistry and Technologies, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia , Viale Regina Elena, 291, 00161 Rome, Italy.
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Forgione
authors.affiliation: Department of Drug Chemistry and Technologies, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lucidi
authors.affiliation: Department of Drug Chemistry and Technologies, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Gebremedhin S
authors.initials: GS
authors.lastname: Hailu
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Vico L. de Crecchio 7, 80138 Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Vico L. de Crecchio 7, 80138 Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carafa
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Vico L. de Crecchio 7, 80138 Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Baratta
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples , Vico L. de Crecchio 7, 80138 Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.affiliation: TES Pharma S.r.l. , Via P. Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giacché
authors.affiliation: TES Pharma S.r.l. , Via P. Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.affiliation: TES Pharma S.r.l. , Via P. Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.affiliation: Department of Drug Chemistry and Technologies, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Antonello
authors.identifier: 0000-0001-9176-2382
authors.initials: A
authors.lastname: Mai
authors.affiliation: Department of Biochemistry and Research Center for Bio-Macromolecules, University of Bayreuth , 95440 Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.affiliation: Department of Drug Chemistry and Technologies, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D056565:Sirtuin 2