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

Marianna Nalli; Laura Di Magno; Yichao Wen; Xin Liu; Michele D'Ambrosio; Michela Puxeddu; Anastasia Parisi; Jessica Sebastiani; Andrea Sorato; Antonio Coluccia; Silvia Ripa; Fiorella Di Pastena; Davide Capelli; Roberta Montanari; Domiziana Masci; Andrea Urbani; Chiara Naro; Claudio Sette; Viviana Orlando; Sara D'Angelo; Stefano Biagioni; Chiara Bigogno; Giulio Dondio; Arianna Pastore; Mariano Stornaiuolo; Gianluca Canettieri; Te Liu; Romano Silvestri; Giuseppe La Regina

doi:10.1021/acsptsci.3c00092

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. eCollection 2023 Jul 14.

Authors

Marianna Nalli¹, Laura Di Magno², Yichao Wen³, Xin Liu⁴, Michele D'Ambrosio¹, Michela Puxeddu¹, Anastasia Parisi¹, Jessica Sebastiani¹, Andrea Sorato¹, Antonio Coluccia¹, Silvia Ripa², Fiorella Di Pastena², Davide Capelli⁵, Roberta Montanari⁵, Domiziana Masci⁶, Andrea Urbani⁶, Chiara Naro^{6

7}, Claudio Sette^{6

7}, Viviana Orlando⁸, Sara D'Angelo⁸, Stefano Biagioni⁸, Chiara Bigogno⁹, Giulio Dondio⁹, Arianna Pastore¹⁰, Mariano Stornaiuolo¹⁰, Gianluca Canettieri², Te Liu³, Romano Silvestri¹, Giuseppe La Regina¹

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
PMCID: PMC10353061 (available on 2024-07-03)
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.