Targeting STAT3 for cancer therapy: definition of mechanisms of action of direct STAT3 inhibitors

Diplôme Thèse Targeting STAT3 for cancer therapy: definition of mechanisms of action of direct STAT3 inhibitors fre 2013-10-10 author Brambilla Lara 730286 director Scapozza Leonardo 600318 director Catapano Carlo 10.13097/archive-ouverte/unige:37048 urn:nbn:ch:unige-370482 Sc. 4598 STAT3 is a cytoplasmic transcription factor that, once activated, conveys extracellular signals to the nucleus. Activation is achieved through Tyr705 phosphorylation that induces dimerization, nuclear translocation and transcriptional activation of target genes. STAT3 can also be phosphorylated on Ser727. Moreover, its hyper-activation has been implicated in several human cancers. Therefore, STAT3 is a good target candidate for development of anticancer drugs. STAT3 inhibitors are usually divided into indirect inhibitors, acting on upstream pathways, and direct inhibitors, directly binding to STAT3. The aim of this work was to investigate the mechanisms of action of different direct STAT3 inhibitors and define a common mode of action. All compounds showed a reduction of pTyr705 and pSer727 as well as an inhibition of proliferation and clonogenicity of cancer cells, although at different concentrations. These results were consistent with a direct binding of the drugs to STAT3-SH2 domain, confirmed by computational models and site-directed mutagenesis. Dewey 615 31 Section des sciences pharmaceutiques 17 false f776f9d3-8b97-493c-a614-aa4435ced6b7 Thesis Restricted ThesisLara-1.pdf 4877465 application/pdf Private 2015-05-21 c86d52f002af2c21d2b8f50dfed522e52a5b9d31dae15fa32d99b047852bce1f restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques

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Targeting STAT3 for cancer therapy: definition of mechanisms of action of direct STAT3 inhibitors				2013	785	3

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Brambilla, Lara