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.

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 / Puxeddu, Michela; Ling, Lele; Ripa, Silvia; D'Ambrosio, Michele; Nalli, Marianna; Parisi, Anastasia; Scio', Pietro; Coluccia, Antonio; Granese, Arianna; Santelli, Martina; Masci, Domiziana; Cuřínová, Petra; Naro, Chiara; Sette, Claudio; Pastore, Arianna; Stornaiuolo, Mariano; Bigogno, Chiara; Dondio, Giulio; DI MAGNO, Laura; Canettieri, Gianluca; Liu, Te; Silvestri, Romano; LA REGINA, Giuseppe. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 67:(2024), pp. 20298-20314. [10.1021/acs.jmedchem.4c01708]

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

Michela Puxeddu
Co-primo
Methodology
;
Silvia Ripa
Co-primo
Methodology
;
Michele D'Ambrosio
Secondo
Methodology
;
Marianna Nalli
Methodology
;
Anastasia Parisi
Methodology
;
Pietro Scio'
Methodology
;
Antonio Coluccia
Methodology
;
Arianna Granese
Methodology
;
Laura Di Magno
Methodology
;
Gianluca Canettieri
Methodology
;
Romano Silvestri
Penultimo
Supervision
;
Giuseppe La Regina
Ultimo
Project Administration
2024

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.
2024
Wnt/β-catenin signaling; colon cancer; drug resistance
01 Pubblicazione su rivista::01a Articolo in rivista
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 / Puxeddu, Michela; Ling, Lele; Ripa, Silvia; D'Ambrosio, Michele; Nalli, Marianna; Parisi, Anastasia; Scio', Pietro; Coluccia, Antonio; Granese, Arianna; Santelli, Martina; Masci, Domiziana; Cuřínová, Petra; Naro, Chiara; Sette, Claudio; Pastore, Arianna; Stornaiuolo, Mariano; Bigogno, Chiara; Dondio, Giulio; DI MAGNO, Laura; Canettieri, Gianluca; Liu, Te; Silvestri, Romano; LA REGINA, Giuseppe. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 67:(2024), pp. 20298-20314. [10.1021/acs.jmedchem.4c01708]
File allegati a questo prodotto
File Dimensione Formato  
Puxeddu_Development_2024.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 7.58 MB
Formato Adobe PDF
7.58 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1727020
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact