Structure–activity relationship and properties optimization of a series of Quinazoline-2,4-diones as inhibitors of the canonical Wnt pathway

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. [Display omitted] •Screening campaign to identify small molecules inhibitors of the canonical Wnt pathway.•Hit compound identification.•Design and synthesis of new analogues to improve in vitro ADME profile of hit compound.•Identification of lead and characterization in vitro and in vivo.•Lead compound as potential candidate for the treatment of Wnt responsive peripheral cancers.