2. Academic Validation
  3. 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

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 Pharmacol Transl Sci. 2023 Jul 3;6(7):1087-1103. doi: 10.1021/acsptsci.3c00092.
Marianna Nalli 1,  Laura Di Magno 2,  Yichao Wen 3,  Xin Liu 4,  Michele D'Ambrosio 1,  Michela Puxeddu 1,  Anastasia Parisi 1,  Jessica Sebastiani 1,  Andrea Sorato 1,  Antonio Coluccia 1,  Silvia Ripa 2,  Fiorella Di Pastena 2,  Davide Capelli 5,  Roberta Montanari 5,  Domiziana Masci 6,  Andrea Urbani 6,  Chiara Naro 6 7,  Claudio Sette 6 7,  Viviana Orlando 8,  Sara D'Angelo 8,  Stefano Biagioni 8,  Chiara Bigogno 9,  Giulio Dondio 9,  Arianna Pastore 10,  Mariano Stornaiuolo 10,  Gianluca Canettieri 2,  Te Liu 3,  Romano Silvestri 1,  Giuseppe La Regina 1
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, 200031 Shanghai, China.
  • 4 Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 200437 Shanghai, China.
  • 5 CNR-Institute of Crystallography, Via Salaria-km 29.300, Monterotondo, 00015 Rome, Italy.
  • 6 Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy.
  • 7 GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy.
  • 8 Department of Biology and Biotechnologies "Charles Darwin", Piazzale Aldo Moro 5, I-00185 Roma, Italy.
  • 9 Aphad SrL, Via della Resistenza 65, 20090 Buccinasco, Italy.
  • 10 Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano, 49, 80131 Naples, Italy.
PMID: 37470018 DOI: 10.1021/acsptsci.3c00092
Abstract

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 N-(heterocyclylphenyl)benzenesulfonamides as β-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 β-catenin and Tcf-4. The crystallographic analysis of the β-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 β-catenin inhibitors as Anticancer agents.

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