Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F25%3A10491819" target="_blank" >RIV/00216208:11160/25:10491819 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=kQ9ICO_E4u" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=kQ9ICO_E4u</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1080/10985549.2024.2438817" target="_blank" >10.1080/10985549.2024.2438817</a>
Alternative languages
Result language
angličtina
Original language name
Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma
Original language description
In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/EH22_008%2F0004607" target="_blank" >EH22_008/0004607: New Technologies for Translational Research in Pharmaceutical Sciences /NETPHARM</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Molecular and Cellular Biology
ISSN
0270-7306
e-ISSN
1098-5549
Volume of the periodical
45
Issue of the periodical within the volume
2
Country of publishing house
US - UNITED STATES
Number of pages
19
Pages from-to
79-97
UT code for WoS article
001382430300001
EID of the result in the Scopus database
2-s2.0-85212957590