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

被引：4

作者：

Nalli, Marianna ^{[1
]}

Di Magno, Laura ^{[2
]}

Wen, Yichao ^{[3
]}

Liu, Xin ^{[4
]}

D'Ambrosio, Michele ^{[1
]}

Puxeddu, Michela ^{[1
]}

Parisi, Anastasia ^{[1
]}

Sebastiani, Jessica ^{[1
]}

Urbani, Andrea ^{[1
,6
]}

Coluccia, Antonio ^{[1
]}

Ripa, Silvia ^{[2
]}

Di Pastena, Fiorella ^{[2
]}

Capelli, Davide ^{[5
]}

Montanari, Roberta ^{[5
]}

Masci, Domiziana ^{[6
]}

Urbani, Andrea ^{[1
,6
]}

Bigogno, Chiara ^{[8
]}

Sette, Claudio ^{[6
,10
]}

Orlando, Viviana ^{[7
]}

D'Angelo, Sara ^{[7
]}

Biagioni, Stefano ^{[7
]}

Bigogno, Chiara ^{[8
]}

Dondio, Giulio ^{[8
]}

Pastore, Arianna ^{[9
]}

Stornaiuolo, Mariano ^{[9
]}

Canettieri, Gianluca ^{[2
]}

Liu, Te ^{[3
]}

Silvestri, Romano ^{[1
]}

La Regina, Giuseppe ^{[1
]}

机构：

[1] Sapienza Univ Rome, Ist Pasteur Italia, Dept Drug Chem & Technol, Lab,Fdn Cenci Bolognetti, I-00185 Rome, Italy

[2] Sapienza Univ Rome, Ist Pasteur Italia, Dept Mol Med, I-00161 Rome, Italy

[3] Shanghai Univ Tradit Chinese Med, Shanghai Geriatr Inst Chinese Med, Shanghai 200031, Peoples R China

[4] Shanghai Univ Tradit Chinese Med, Yueyang Hosp Integrated Tradit Chinese & Western, Dept Dermatol, Shanghai 200437, Peoples R China

[5] CNR, Inst Crystallog, I-00015 Rome, Italy

[6] Univ Cattolica Sacro Cuore, Dept Basic Biotechnol Sci, Intensivol & Perioperat Clin, I-00168 Rome, Italy

[7] Dept Biol & Biotechnol Charles Darwin, I-00185 Rome, Italy

[8] Aphad SrL, I-20090 Buccinasco, Italy

[9] Univ Naples Federico II, Dept Pharm, I-80131 Naples, Italy

[10] Fdn Policlin Univ A Gemelli, GSTeP Organoids Res Core Facil, IRCCS, I-00168 Rome, Italy

来源：

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE | 2023年 / 6卷 / 07期

关键词：

beta-catenin; c-MYC; T-cell factor; colorectal cancer; sulfonamide; crystal structure; HEDGEHOG PATHWAY; CANCER; INHIBITORS; COMPLEX; DEGRADATION; ACTIVATION; MUTATIONS; DISCOVERY; DESIGN; GROWTH;

D O I：

10.1021/acsptsci.3c00092

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1087 / 1103

页数：17

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