Targeting beta-catenin and dishevelled protein as a synergistic strategy against colorectal cancer

Research project funded by AIRC.

We aim to obtain compounds inhibitors of the Wnt/β-catenin pathway with efficacy for CRC cancer cells. The identified modulators have to be endowed with physicochemical and ADME properties required for drug candidates.

The experimental plan is therefore: (1) to test the effect of the different modulators on the Wnt/TCF signaling and to perform functional analyses by using reporter vectors and endogenous targets; (2) to test the effect of the different inhibitors of NHERF1 on DVL; (3) refinement of pharmacophores by means of the Wnt/β-Catenin and DVL structural information; (4) virtual screening studies of compound libraries, selection and synthesis of analogues; (5) in vitro test of Wnt-β/TCF and DVL modulators; (6) CRC inhibition by singly and in drug combination; (7) optimization of the drug-like properties of most powerful drugs; (8) in vivo test in APCMin/+ mice.

We expect to identify compounds as potential drug for CRC treatment and combinations thereof for CRC in vivo studies.

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