Identification and characterization of new chemical entities which specifically interfere with the mTOR signal transduction pathway using a novel screening system

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Projektnummer

8963.1;4 PFLS-LS

Projekttitel

Identification and characterization of new chemical entities which specifically interfere with the mTOR signal transduction pathway using a novel screening system

Projekttitel Englisch

Identification and characterization of new chemical entities which specifically interfere with the mTOR signal transduction pathway using a novel screening system

Texte zu diesem Projekt

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Erfasste Texte

Kategorie	Text
Kurzbeschreibung (Englisch)	Identification and characterization of new chemical entities which specifically interfere with the mTOR signal transduction pathway using a novel screening system
Abstract (Englisch)	Mammalian Target Of Rapamycin (mTOR) is a protein with protein kinase activity which integrates growth stimulatory and oxygen, nutrients and energy sensing pathways. The signaling pathways that activate mTOR are altered in many human cancers. mTOR activation leads to increased mRNA translation and protein synthesis which stimulates cell proliferation, cell survival and migration. Moreover, the activation of mTOR can also lead to the release of growth factors and cytokines which in turn affect tumor angiogenesis. Not surprising, mTOR and its upstream altered activators have been identified as one of the most attractive target areas in oncology. Rapamycin has been isolated about 30 years ago as a potent antiproliferative compound with immunosuppressive activity. The target of Rapamycin, mTOR has been identified in 1991 at the Biocenter in Basel and the recognition that many upstream regulators of mTOR are altered in human tumors has lead to an interest to study Rapamycin and recent derivatives as anticancer agents. So far Rapamycin and its analogues are the only known inhibitors of mTOR and have shown efficacy in cancer trials. New compound classes with new modes of action and to overcome some of the shortcomings of Rapamycins are required to fully exploit the therapeutic potential of mTOR as a target to treat human diseases. We will use a unique cellular screening system recently developed at the Moroni lab at the University of Basel to identify novel modulators of mTOR and study compounds for direct or indirect inhibiton of the mTOR function. In this application, we propose a) to test over 100¿000 Actelion compounds using the novel TOR-pathway mutants; b) to analyze potential hits biochemically for effect on downstream TOR targets; and c) to develop the cellular system further for use in additional drug discovery approaches.

Kategorie

Text

Kurzbeschreibung
(Englisch)

Identification and characterization of new chemical entities which specifically interfere with the mTOR signal transduction pathway using a novel screening system

Abstract
(Englisch)

Mammalian Target Of Rapamycin (mTOR) is a protein with protein kinase activity which integrates growth stimulatory and oxygen, nutrients and energy sensing pathways. The signaling pathways that activate mTOR are altered in many human cancers. mTOR activation leads to increased mRNA translation and protein synthesis which stimulates cell proliferation, cell survival and migration. Moreover, the activation of mTOR can also lead to the release of growth factors and cytokines which in turn affect tumor angiogenesis. Not surprising, mTOR and its upstream altered activators have been identified as one of the most attractive target areas in oncology. Rapamycin has been isolated about 30 years ago as a potent antiproliferative compound with immunosuppressive activity. The target of Rapamycin, mTOR has been identified in 1991 at the Biocenter in Basel and the recognition that many upstream regulators of mTOR are altered in human tumors has lead to an interest to study Rapamycin and recent derivatives as anticancer agents. So far Rapamycin and its analogues are the only known inhibitors of mTOR and have shown efficacy in cancer trials. New compound classes with new modes of action and to overcome some of the shortcomings of Rapamycins are required to fully exploit the therapeutic potential of mTOR as a target to treat human diseases. We will use a unique cellular screening system recently developed at the Moroni lab at the University of Basel to identify novel modulators of mTOR and study compounds for direct or indirect inhibiton of the mTOR function. In this application, we propose a) to test over 100¿000 Actelion compounds using the novel TOR-pathway mutants; b) to analyze potential hits biochemically for effect on downstream TOR targets; and c) to develop the cellular system further for use in additional drug discovery approaches.