Discovery of 14‐3‐3 Protein–Protein Interaction Inhibitors that Sensitize Multidrug‐Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693
2014
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Аутори:
Mori, MattiaVignaroli, Giulia
Cau, Ylenia
Dinić, Jelena
Hill, Richard
Rossi, Matteo
Colecchia, David
Pešić, Milica
Link, Wolfgang
Chiariello, Mario
Ottmann, Christian
Botta, Maurizio
Тип документа:
Чланак у часопису (Рецензирана верзија)
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© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Метаподаци
Приказ свих података о документуАпстракт:
14-3-3 is a family of highly conserved adapter proteins that is attracting much interest among medicinal chemists. Small-molecule inhibitors of 14-3-3 protein-protein interactions (PPIs) are in high demand, both as tools to increase our understanding of 14-3-3 actions in human diseases and as leads to develop innovative therapeutic agents. Herein we present the discovery of novel 14-3-3 PPI inhibitors through a multidisciplinary strategy combining molecular modeling, organic synthesis, image-based high-content analysis of reporter cells, and in vitro assays using cancer cells. Notably, the two most active compounds promoted the translocation of c-Abl and FOXO pro-apoptotic factors into the nucleus and sensitized multidrug-resistant cancer cells to apoptotic inducers such as doxorubicin and the pan-Akt inhibitor GSK690693, thus becoming valuable lead candidates for further optimization. Our results emphasize the possible role of 14-3-3 PPI inhibitors in anticancer combination therapies.
Напомена:
This is the peer-reviewed version of the following article: Mori M, Vignaroli G, Cau Y, et al. Discovery of 14-3-3 protein-protein interaction inhibitors that sensitize multidrug-resistant cancer cells to doxorubicin and the Akt inhibitor GSK690693. ChemMedChem. 2014;9(5):973-983. doi:10.1002/ cmdc.201400044, which has been published in final form at https:// doi.org/10.1002/cmdc.201400044. This article may be used for non- commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-Archiving.
Related to: https://radar.ibiss.bg.ac.rs/handle/123456789/2215.
Кључне речи:
antitumor agents; cancer; doxorubicin; inhibitors; multidrug resistance; protein-protein interactionsИзвор:
ChemMedChem, 2014, 9, 5, 973-983Финансирање / пројекти:
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- Fundação para a Ciência e a Tecnologia (SFRH/BPD/84634/2012)
- Lead Discovery Siena, Srl
- COST Action CM1106 (Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells)
DOI: 10.1002/cmdc.201400044
ISSN: 1860-7187
PubMed: 24715717
WoS: 000335001700012
Scopus: 2-s2.0-84899975034
URI
https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cmdc.201400044https://radar.ibiss.bg.ac.rs/123456789/3886