Benzofuran derivatives as anticancer inhibitors of mTOR signaling.
A series of 32 derivatives and isosteres of the mTOR inhibitor 2 were synthesized and compared for their cytotoxicity in radioresistant SQ20B cancer cell line. Several of these compounds, in particular 30b, were significantly more cytotoxic than 2. Importantly, 30b was shown to block both mTORC1 and Akt signaling, suggesting insensitivity to the resistance associated to Akt overactivation observed with rapamycin derivatives currently used in clinic.
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Christophe
C
Salomé
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Nigel
N
Ribeiro
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Thierry
T
Chavagnan
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Frédéric
F
Thuaud
AAREC Filia Research, 1 Place Paul Verlaine, 92100 Boulogne-Billancourt, France.
Maria
M
Serova
AAREC Filia Research, 1 Place Paul Verlaine, 92100 Boulogne-Billancourt, France.
Armand
A
de Gramont
Departments of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HP, Clichy, France.
Sandrine
S
Faivre
Departments of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HP, Clichy, France.
Eric
E
Raymond
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France. Electronic address: desaubry@unistra.fr.
Laurent
L
Désaubry
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D001572:Benzofurans; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C105430:benzofuran
Benzofuran; Cancer; Cytotoxicity; Rapamycin; mTOR