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Optimization of Peptidomimetics as Selective Inhibitors for the ?-Catenin/T-Cell Factor Protein-Protein Interaction.

ABSTRACT: The ?-catenin/T-cell factor (Tcf) protein-protein interaction (PPI) plays a critical role in the ?-catenin signaling pathway which is hyperactivated in many cancers and fibroses. Based on compound 1, which was designed to target the Tcf4 G13ANDE17 binding site of ?-catenin, extensive structure-activity relationship studies have been conducted. As a result, compounds 53 and 57 were found to disrupt the ?-catenin/Tcf PPI with the Ki values of 0.64 and 0.44 ?M, respectively, and exhibit good selectivity for ?-catenin/Tcf over ?-catenin/E-cadherin and ?-catenin/adenomatous polyposis coli (APC) PPIs. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) cell viability assays revealed that 56, the ethyl ester of 53, was more potent than 53 in inhibiting viability of most of the Wnt/?-catenin hyperactive cancer cells. Further cell-based studies indicated that 56 disrupted the ?-catenin/Tcf PPI without affecting the ?-catenin/E-cadherin and ?-catenin/APC PPIs, suppressed transactivation of Wnt/?-catenin signaling in dose-dependent manners, and inhibited migration and invasiveness of Wnt/?-catenin-dependent cancer cells.

SUBMITTER: Wang Z 

PROVIDER: S-EPMC6931396 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Optimization of Peptidomimetics as Selective Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction.

Wang Zhen Z   Zhang Min M   Wang Jin J   Ji Haitao H  

Journal of medicinal chemistry 20190321 7

The β-catenin/T-cell factor (Tcf) protein-protein interaction (PPI) plays a critical role in the β-catenin signaling pathway which is hyperactivated in many cancers and fibroses. Based on compound 1, which was designed to target the Tcf4 G<sup>13</sup>ANDE<sup>17</sup> binding site of β-catenin, extensive structure-activity relationship studies have been conducted. As a result, compounds 53 and 57 were found to disrupt the β-catenin/Tcf PPI with the K<sub>i</sub> values of 0.64 and 0.44 μM, resp  ...[more]

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