Novel aminotetrazole derivatives as selective STAT3 non-peptide inhibitors.
The development of inhibitors blocking STAT3 transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases. In this context, the selectivity of inhibitors against the STAT1 transcription factor is crucial as STAT3 and STAT1 play opposite roles in the apoptosis of tumor cells and polarization of the immune response. A structure-based virtual screening followed by a luciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor. An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established. Optimization of the hit compound leads to 23. This compound inhibits growth and survival of cells with STAT3 signaling pathway while displaying a minimal effect on STAT1 signaling. Moreover, it prevents lymphocyte T polarization into Th17 and Treg without affecting their differentiation into Th1 lymphocyte.
Inserm 1098, EFS Bourgogne Franche Comté, University of Franche-Comté, IFR133, 8 rue du Dr Girod, 25020 Besançon, France. Electronic address: Jean-Rene.PALLANDRE@efs.sante.fr.
Jean-René
JR
Pallandre
Inserm 1098, EFS Bourgogne Franche Comté, University of Franche-Comté, IFR133, 8 rue du Dr Girod, 25020 Besançon, France. Electronic address: xtoph.borg@gmail.com.
Christophe
C
Borg
Laboratory for Therapeutical Innovation, UMR 7200 Université de Strasbourg/CNRS, MEDALIS Drug Discovery Center, F-67400 Illkirch, France. Electronic address: rognan@unistra.fr.
Didier
D
Rognan
Nanomedicine Lab, EA - 4662, UFR SMP 19 rue Ambroise Paré Université de Franche Comté, 25030 Besançon Cedex, France. Electronic address: thibautboibessot@hotmail.fr.
Thibault
T
Boibessot
Nanomedicine Lab, EA - 4662, UFR SMP 19 rue Ambroise Paré Université de Franche Comté, 25030 Besançon Cedex, France. Electronic address: vincent.luzet@univ-fcomte.fr.
Vincent
V
Luzet
Laboratoire Chrono Environnement UMR CNRS 6249, Faculté des Sciences et Techniques, La Bouloie, Université de Franche-Comté, 25030, Besançon Cedex, France; Institute of Physics, National Academy of Sciences of Ukraine, Prospect Nauki, 46, Kyiv, 03039, Ukraine. Electronic address: yesint4@gmail.com.
Semen
S
Yesylevskyy
Laboratoire Chrono Environnement UMR CNRS 6249, Faculté des Sciences et Techniques, La Bouloie, Université de Franche-Comté, 25030, Besançon Cedex, France. Electronic address: christophe.ramseyer@univ-fcomte.fr.
Christophe
C
Ramseyer
Nanomedicine Lab, EA - 4662, UFR SMP 19 rue Ambroise Paré Université de Franche Comté, 25030 Besançon Cedex, France. Electronic address: marc.pudlo@univ-fcomte.fr.
Marc
M
Pudlo
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D013777:Tetrazoles
Aminotetrazole; Anticancer drug; Inflammation; STAT3; Small-molecule inhibitor