title: Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway.
abstract: The canonical Wnt signaling pathway plays a fundamental role in embryonic as well as in adult development. Consequently, dysregulation of the pathway has been linked to a wide spectrum of pathological conditions. In a program aimed at the identification of small molecule inhibitors of the canonical Wnt pathway we identified a series of 2-aminopyrimidine derivatives which specifically inhibited the pathway with minimal or no sign of cellular toxicity. The hit molecules 1 and 2 showed promising inhibitory activity with IC50 values of approximately 10 μM, but low solubility and metabolic stability. During the early stage of the hit series exploration, the pyrimidine core was variously decorated to obtain active compounds with a better physico-chemical profile. In particular, compound 13 showed Wnt inhibition activity comparable to hit molecules 1 and 2, with improved physico-chemical properties. Therefore, this series of compounds may be considered a promising starting point for the design of novel small molecule inhibitors of the canonical Wnt pathway.
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy. Electronic address: fabio.delbello@unicam.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Aniket
authors.initials: A
authors.lastname: Farande
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.affiliation: Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.affiliation: Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Benicchi
authors.affiliation: Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappelli
authors.affiliation: Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Nencini
authors.affiliation: Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Salerno
authors.affiliation: Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Thomas
authors.affiliation: Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Massimilano
authors.initials: M
authors.lastname: Travagli
authors.affiliation: Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Varrone
mesh_terms: D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D011743:Pyrimidines; D051176:beta Catenin; C012180:2-aminopyrimidine
keywords: Aminopyrimidine; Small molecule inhibitors; Wnt signaling pathway; β-Catenin