Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases.

Détails

ID Serval
serval:BIB_A5C1DEE4954D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases.
Périodique
Molecular cancer therapeutics
Auteur(s)
Murone M., Vaslin Chessex A., Attinger A., Ramachandra R., Shetty S.J., Daginakatte G., Sengupta S., Marappan S., Dhodheri S., Rigotti S., Bachhav Y., Brienza S., Traxler P., Lang M., Aguet M., Zoete V., Michielin O., Nicholas C., Johnson F.M., Ramachandra M., McAllister A.
ISSN
1538-8514 (Electronic)
ISSN-L
1535-7163
Statut éditorial
Publié
Date de publication
10/2016
Peer-reviewed
Oui
Volume
15
Numéro
10
Pages
2334-2343
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non-small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334-43. ©2016 AACR.

Mots-clé
Animals, Antineoplastic Agents/chemistry, Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Cell Line, Tumor, Disease Models, Animal, Drug Design, Humans, Janus Kinases/antagonists & inhibitors, Janus Kinases/chemistry, Mice, Molecular Conformation, Molecular Docking Simulation, Molecular Dynamics Simulation, Neoplasm Metastasis, Neoplasms/drug therapy, Neoplasms/metabolism, Neoplasms/pathology, Protein Kinase Inhibitors/chemistry, Protein Kinase Inhibitors/pharmacology, Receptor Protein-Tyrosine Kinases/antagonists & inhibitors, Receptor Protein-Tyrosine Kinases/chemistry, STAT3 Transcription Factor/metabolism, Signal Transduction/drug effects, Tumor Burden/drug effects, Xenograft Model Antitumor Assays, src-Family Kinases/antagonists & inhibitors, src-Family Kinases/chemistry
Pubmed
Web of science
Open Access
Oui
Création de la notice
05/02/2018 14:40
Dernière modification de la notice
20/08/2019 16:10
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