Development of <i>N</i>-(4-(1<i>H</i>-Imidazol-1-yl)phenyl)-4-chlorobenzenesulfonamide, a Novel Potent Inhibitor of β-Catenin with Enhanced Antitumor Activity and Metabolic Stability
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.
Authors
- Laura Di Magno (ORCID: https://orcid.org/0000-0001-9446-8752)
- Domiziana Masci (ORCID: https://orcid.org/0000-0002-5615-5111)
- Chiara Bigogno
- Claudio Sette (ORCID: https://orcid.org/0000-0003-2864-8266)
- Petra Cuřínová (ORCID: https://orcid.org/0000-0001-8264-7032)
- Chiara Naro (ORCID: https://orcid.org/0000-0002-3135-3218)
- Mariano Stornaiuolo (ORCID: https://orcid.org/0000-0003-2200-5083)
- Lele Ling (ORCID: https://orcid.org/0000-0002-6782-4181)
- Maurice Santelli (ORCID: https://orcid.org/0000-0002-0033-0072)
- Silvia Ripa
- Gianluca Canettieri (ORCID: https://orcid.org/0000-0001-6694-2613)
- Romano Silvestri (ORCID: https://orcid.org/0000-0003-2489-0178)
- Antonio Coluccia (ORCID: https://orcid.org/0000-0002-7940-8206)
- Arianna Granese (ORCID: https://orcid.org/0000-0002-0598-5991)
- Marianna Nalli (ORCID: https://orcid.org/0000-0003-2774-6868)
- Arianna Pastore (ORCID: https://orcid.org/0000-0002-2436-658X)
- Giuseppe La Regina (ORCID: https://orcid.org/0000-0003-3252-1161)
- Michela Puxeddu (ORCID: https://orcid.org/0000-0002-0024-596X)
- Michele D’Ambrosio (ORCID: https://orcid.org/0000-0002-8651-6256)
- Giulio Dondio (ORCID: https://orcid.org/0000-0001-5023-3804)
- Pietro Sciò
- Te Liu (ORCID: https://orcid.org/0000-0003-3976-3489)
- Anastasia Parisi
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Shanghai Jiao Tong University (CN)
- Agostino Gemelli University Polyclinic (IT)
- Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai First People's Hospital (CN)
- Istituto Pasteur (IT)
- University of Naples Federico II (IT)
- Sapienza University of Rome (IT)
- University of Chemistry and Technology, Prague (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01708
- Citations
- 2
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Sapienza Università di Roma
- Istituto Pasteur-Fondazione Cenci Bolognetti
- Fondazione Umberto Veronesi
- Associazione Italiana per la Ricerca sul Cancro
- Università Cattolica del Sacro Cuore
- China Academy of Traditional Chinese Medicine
- Ministero dell'Università e della Ricerca