title: Structure-activity relationship and properties optimization of a series of quinazoline-2,4-diones as inhibitors of the canonical Wnt pathway.
abstract: Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. Electronic address: arianna.nencini@gmail.com.
authors.forename: Arianna
authors.initials: A
authors.lastname: Nencini
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Pratelli
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Aptuit S.r.l., Via Alessandro Fleming 4, 37135 Verona, Italy.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Quinn
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Salerno
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tunici
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: De Robertis
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Valensin
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Mennillo
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Children's Tumor Foundation, 95 Pine Street, 16th Floor, New York, 10005 NY, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Bakker
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Tespharma s.r.l., Taverne di Corciano 20, Perugia, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Benicchi
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappelli
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Turlizzi
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Novartis Vaccines, Via Fiorentina, 53100 Siena, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Nibbio
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Nicola P
authors.initials: NP
authors.lastname: Caradonna
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Merck KgaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Ugo
authors.initials: U
authors.lastname: Zanelli
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Andreini
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Magnani
authors.affiliation: Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Glaxo Smith Kline Neural Pathways DPU, 11 Biopolis Way, The Helios, 03-01/02, Singapore 138667, Singapore.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Varrone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines
keywords: Glioblastoma; Small molecule; Structure–activity relationship; Wnt pathway; β-catenin