2. Academic Validation
  3. Development of N-(4-(1 H-Imidazol-1-yl)phenyl)-4-chlorobenzenesulfonamide, a Novel Potent Inhibitor of β-Catenin with Enhanced Antitumor Activity and Metabolic Stability

Development of N-(4-(1 H-Imidazol-1-yl)phenyl)-4-chlorobenzenesulfonamide, a Novel Potent Inhibitor of β-Catenin with Enhanced Antitumor Activity and Metabolic Stability

  • J Med Chem. 2024 Nov 28;67(22):20298-20314. doi: 10.1021/acs.jmedchem.4c01708.
Michela Puxeddu 1,  Lele Ling 2,  Silvia Ripa 3,  Michele D'Ambrosio 1,  Marianna Nalli 1,  Anastasia Parisi 1,  Pietro Sciò 1,  Antonio Coluccia 1,  Arianna Granese 1,  Martina Santelli 4,  Domiziana Masci 4,  Petra Cuřínová 5,  Chiara Naro 4 6,  Claudio Sette 4 6,  Arianna Pastore 7,  Mariano Stornaiuolo 7,  Chiara Bigogno 8,  Giulio Dondio 8,  Laura Di Magno 3,  Gianluca Canettieri 3,  Te Liu 9,  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 Department of Acupuncture and Moxibustion, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 200086 Shanghai, China.
  • 3 Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy.
  • 4 Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy.
  • 5 Department of Organic Chemistry, University of Chemistry and Technology Prague, Technická 5, 16628 Prague 6, Czech Republic.
  • 6 GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy.
  • 7 Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy.
  • 8 Aphad SrL, Via della Resistenza 65, 20090 Buccinasco, Italy.
  • 9 Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, 200031 Shanghai, China.
PMID: 39508273 DOI: 10.1021/acs.jmedchem.4c01708
Abstract

The potential as a Cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the β-catenin armadillo repeat domain was not exhaustively explored. In order to get more insight, we synthesized novel N-(heterocyclylphenyl)benzenesulfonamides 6-28. The new compounds significantly inhibited Wnt-dependent transcription as well as SW480 and HCT116 Cancer cell proliferation. Compound 25 showed binding mode consistent with this hotspot binding region. Compound 25 inhibited the growth of SW480 and HCT116 Cancer cells with IC50's of 2 and 0.12 μM, respectively, and was superior to the reference compounds 5 and 5-FU. 25 inhibited the growth of HCT-116 xenografted in BALB/Cnu/nu mice, reduced the expression of the proliferation marker Ki67, and significantly affected the expression of cancer-related genes. After incubation with human and mouse liver microsomes, 25 showed a higher metabolic stability than 5. Compound 25 aims to be a promising lead for the development of colorectal cancer Anticancer therapies.

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