Despite intensive efforts, no inhibitors of the Wnt/beta-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel N-(heterocyclylphenyl)benzenesulfonamides as beta-catenin inhibitors. Compounds 5-10 showed strong inhibition of the luciferase activity. Compounds 5 and 6 inhibited the MDA-MB-231, HCC1806, and HCC1937 TNBC cells. Compound 9 induced in vitro cell death in SW480 and HCT116 cells and in vivo tumorigenicity of a human colorectal cancer line HCT116. In a co-immunoprecipitation study in HCT116 cells transfected with Myc-tagged T-cell factor 4 (Tcf-4), compound 9 abrogated the association between beta-catenin and Tcf-4. The crystallographic analysis of the beta-catenin Armadillo repeats domain revealed that compound 9 and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound 9 is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of beta-catenin inhibitors as anticancer agents.
Nalli, M., Di Magno, L., Wen, Y., Liu, X., D'Ambrosio, M., Puxeddu, M., Parisi, A., Sebastiani, J., Sorato, A., Coluccia, A., Ripa, S., Di Pastena, F., Capelli, D., Montanari, R., Masci, D., Urbani, A., Naro, C., Sette, C., Orlando, V., D'Angelo, S., Biagioni, S., Bigogno, C., Dondio, G., Pastore, A., Stornaiuolo, M., Canettieri, G., Liu, T., Silvestri, R., La Regina, G., Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent, <<ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE>>, 2023; 6 (7): 1087-1103. [doi:10.1021/acsptsci.3c00092] [https://hdl.handle.net/10807/256154]
Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as an Anticancer Agent
Sebastiani, Jessica;Masci, Domiziana;Urbani, Andrea;Naro, Chiara;Sette, ClaudioPenultimo
;La Regina, GiuseppeUltimo
2023
Abstract
Despite intensive efforts, no inhibitors of the Wnt/beta-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel N-(heterocyclylphenyl)benzenesulfonamides as beta-catenin inhibitors. Compounds 5-10 showed strong inhibition of the luciferase activity. Compounds 5 and 6 inhibited the MDA-MB-231, HCC1806, and HCC1937 TNBC cells. Compound 9 induced in vitro cell death in SW480 and HCT116 cells and in vivo tumorigenicity of a human colorectal cancer line HCT116. In a co-immunoprecipitation study in HCT116 cells transfected with Myc-tagged T-cell factor 4 (Tcf-4), compound 9 abrogated the association between beta-catenin and Tcf-4. The crystallographic analysis of the beta-catenin Armadillo repeats domain revealed that compound 9 and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound 9 is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of beta-catenin inhibitors as anticancer agents.
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