AntiDVL Drugs

DVL is a FZD pathway-specific signaling module and the molecular interface between DVL and FZD is dependent on specific PDZ domain interactions. Thus, the internal PDZ ligand domain of FZD is a potentially attractive target for drug design [109]. Indeed, a recent ligand screen identified an indole-3-carbinol compound (NSC668036 from the National Cancer Institute small-molecule library) that interfered with the DVL PDZ domain and disturbed binding and communication between FZD and DVL [110]. In Xenopus laevis-based assays, this compound was capable of inhibiting WNT-3A-induced signaling. Further development yielded FJ9 ((2-(1-hydroxypentyl)-3-(2-phenylethyl) - 6 - methyl)indole - 5 - carboxylic acid), a non - electrophilic indole - 2 -carbinol-based compound that inhibits the interaction between FZD and the PDZ domain of DVL and blocks the growth of tumor cells in a P -catenin -dependent manner [111]. The same structural approach was then further developed to optimize indole-2-carbinol-based compounds that selectively attack the DVL1-TCF pathway in cells and to implement a screening platform for developing compounds with higher potency, efficacy, and selectivity [112].

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