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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22310%2F24%3A43931122" target="_blank" >RIV/60461373:22310/24:43931122 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.4c01708" target="_blank" >https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.4c01708</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.4c01708" target="_blank" >10.1021/acs.jmedchem.4c01708</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the beta-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&apos;s of 2 and 0.12 mu M, 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the beta-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&apos;s of 2 and 0.12 mu M, 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

—

Návaznosti

N - Vyzkumna aktivita podporovana z neverejnych zdroju

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JOURNAL OF MEDICINAL CHEMISTRY

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

67

Číslo periodika v rámci svazku

22

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

20298-20314

Kód UT WoS článku

001350014100001

EID výsledku v databázi Scopus

2-s2.0-85208709914