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
  • 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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