Discovery of 14-3-3 Protein- Protein Interaction Inhibitors that Sensitize Multidrug- Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693
2014
Autori:
Mori, MattiaVignaroli, Giulia
Cau, Ylenia
Dinić, Jelena
Hill, Richard
Rossi, Matteo
Colecchia, David
Pešić, Milica
Link, Wolfgang
Chiariello, Mario
Ottmann, Christian
Botta, Maurizio
Tip dokumenta:
Članak u časopisu (Objavljena verzija)
,
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
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.
Napomena:
Related to: https://radar.ibiss.bg.ac.rs/handle/123456789/3886.
Ključne reči:
antitumor agents; cancer; doxorubicin; inhibitors; multidrug resistance; protein-protein interactionsIzvor:
Chemmedchem, 2014, 9, 5, SI, 973-983Finansiranje / projekti:
- Identifikacija molekularnih markera za predikciju progresije tumora, odgovora na terapiju i ishoda bolesti (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