Author: Pratelli, Carmela ; Mennillo, Federica ; De Robertis, Alessandra ; Benicchi, Tiziana ; Andreini, Matteo ; Salerno, Massimiliano ; Tunici, Patrizia ; Varrone, Maurizio ; Cappelli, Federico ; Zanelli, Ugo ; Magnani, Matteo ; Nibbio, Martina ; Rossi, Marco ; Quinn, Joanna M ; Bakker, Annette ; Valensin, Silvia ; Caradonna, Nicola P ; Nencini, Arianna ; Turlizzi, Elisa

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.

16 Aug 2013·Organic Process Research & Development

Process Development and Scale-Up for the Preparation of the 1-Methyl-quinazoline-2,4-dione Wnt Inhibitor SEN461

Author: Wiedenau, Paul ; Panico, Alessandro ; Betti, Matteo ; Genesio, Eva ; Sanna Coccone, Salvatore

The Wnt inhibitor SEN461 I (R = MeOCH₂CO) was prepared in nine steps on multihundred gram scale; the intermediates were solids isolable by filtration which did not require chromatog., and the synthesis required no specialized equipment, highly hazardous reagents, or cryogenic or thermal reactions.A linear route to GMP intermediate I (R = tert-butoxycarbonyl) was generated with reduced cost and similar yield to a previous route; GMP process development for the phase 1 clin. batch campaign was undertaken.

01 Jul 2013·Molecular Cancer Therapeutics

Identification and Characterization of a Small-Molecule Inhibitor of Wnt Signaling in Glioblastoma Cells

Article

Author: Pendharkar, Vishal ; Salerno, Massimiliano ; Varrone, Maurizio ; Jing Tai, Shi ; Liu, Boping ; Benicchi, Tiziana ; Giordano, Cinzia ; Nencini, Arianna ; Bakker, Annette ; Valensin, Silvia ; He, Xi ; De Robertis, Alessandra ; De Rosa, Antonella ; Verani, Margherita ; Caricasole, Andrea ; Cheong, Seong-Moon ; Rossi, Marco ; Sangthongpitag, Kanda ; Pratelli, Carmela ; Mee Ng, Fui ; Wen Then, Siew ; Tunici, Patrizia ; Hill, Jeffrey

AbstractGlioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than 1 year. Although canonical Wnt pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, β-catenin, or Axin proteins), an increasing number of studies suggest that elevated Wnt signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of Wnt signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to Wnt inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical Wnt signaling and associated proliferative responses in GBM cells. Here, we show that the small molecule SEN461 inhibits the canonical Wnt signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced Axin stabilization, increased β-catenin phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized Wnt signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small-molecule–mediated inhibition of Wnt signaling may be a potential approach for GBM therapeutics. Mol Cancer Ther; 12(7); 1180–9. ©2013 AACR.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Preclinical	Italy	Siena Biotech SpA	01 May 2015

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