Nalli Marianna, Di Magno Laura, Wen Yichao, Liu Xin, D'Ambrosio Michele, Puxeddu Michela, Parisi Anastasia, Sebastiani Jessica, Sorato Andrea, Coluccia Antonio, Ripa Silvia, Di Pastena Fiorella, Capelli Davide, Montanari Roberta, Masci Domiziana, Urbani Andrea, Naro Chiara, Sette Claudio, Orlando Viviana, D'Angelo Sara, Biagioni Stefano, Bigogno Chiara, Dondio Giulio, Pastore Arianna, Stornaiuolo Mariano, Canettieri Gianluca, Liu Te, Silvestri Romano, La Regina Giuseppe
Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine Sapienza, University of Rome, Viale Regina Elena 291, I-00161 Rome, Italy.
ACS Pharmacol Transl Sci. 2023 Jul 3;6(7):1087-1103. doi: 10.1021/acsptsci.3c00092. eCollection 2023 Jul 14.
Despite intensive efforts, no inhibitors of the Wnt/β-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel -(heterocyclylphenyl)benzenesulfonamides as β-catenin inhibitors. Compounds - showed strong inhibition of the luciferase activity. Compounds and inhibited the MDA-MB-231, HCC1806, and HCC1937 TNBC cells. Compound 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 abrogated the association between β-catenin and Tcf-4. The crystallographic analysis of the β-catenin Armadillo repeats domain revealed that compound and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of β-catenin inhibitors as anticancer agents.
尽管付出了巨大努力，但迄今为止，尚无Wnt/β-连环蛋白信号通路抑制剂被批准用于癌症的临床治疗。我们合成了新型的-(杂环苯基)苯磺酰胺作为β-连环蛋白抑制剂。化合物-对荧光素酶活性表现出强烈抑制作用。化合物 和 抑制了MDA-MB-231、HCC1806和HCC1937三阴性乳腺癌细胞。化合物 在SW480和HCT116细胞中诱导了体外细胞死亡，并抑制了人结肠癌细胞系HCT116的体内致瘤性。在用Myc标签的T细胞因子4（Tcf-4）转染的HCT116细胞进行的共免疫沉淀研究中，化合物 消除了β-连环蛋白与Tcf-4之间的结合。β-连环蛋白犰狳重复结构域的晶体学分析表明，化合物 和Tcf-4在靠近Lys508的热点结合区域内共享一个共同的结合位点。据我们所知，化合物 是该区域第一个被报道的小分子配体。这些结果突出了这类新型β-连环蛋白抑制剂作为抗癌药物的潜力。
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