Benzofuran derivatives as a novel class of inhibitors of mTOR signaling.
High-throughput screening (HTS) hit 1 was previously identified as an inhibitor of the Akt/mTOR (Akt/mammalian target of rapamycin) signaling, which is a major target in oncology. The cytotoxicity of 1 was determined on a panel of human cancer cells lines with an IC₅₀ comprised between 30 and 140 μM. Subsequent structure--activity relationship (SAR) studies led us to the identification of compounds that displayed an enhanced cytotoxicity. We demonstrated also that these molecules directly bind to mTOR complex 1 (mTORC1) and inhibit its kinase activity.
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Christophe
C
Salomé
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Vanessa
V
Narbonne
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Nigel
N
Ribeiro
Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
Frédéric
F
Thuaud
Department of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HP, Clichy, France.
Maria
M
Serova
Department of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HP, Clichy, France.
Armand
A
de Gramont
Department of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HP, Clichy, France.
Sandrine
S
Faivre
Department 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
D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015398:Signal Transduction / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D001572:Benzofurans; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
Benzofuran; Cytotoxicity; mTOR; mTORC1