Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 17; pp. 5725 - 5733
• Main Authors: Del Bello, Fabio, Farande, Aniket, Giannella, Mario, Piergentili, Alessandro, Quaglia, Wilma, Benicchi, Tiziana, Cappelli, Federico, Nencini, Arianna, Salerno, Massimiliano, Thomas, Russell J., Travagli, Massimilano, Varrone, Maurizio
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2015
• Subjects: Aminopyrimidine; beta Catenin - metabolism; Humans; Molecular Structure; Pyrimidines - metabolism; Pyrimidines - pharmacology; Small molecule inhibitors; Structure-Activity Relationship; Wnt signaling pathway; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - genetics; β-Catenin; SAR/SPR; Wnt signaling pathway; TNKS; CK1; MW; TLC; LRP; PAMPA; Small molecule inhibitors; CYP3A4; LEF; ppm; Aminopyrimidine; PORCN; APC; Fz; GSK3; UPLC; TCF; TOF-MS; FPSA; β-Catenin
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.07.015

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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 10μM, 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.