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A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells

Abstract : Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187307
Contributor : Laurent Jonchère <>
Submitted on : Wednesday, August 26, 2015 - 3:11:58 PM
Last modification on : Thursday, October 8, 2020 - 3:10:04 AM

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Amelie Fouque, Olivier Delalande, Mickael Jean, Remy Castellano, Emmanuelle Josselin, et al.. A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells. Journal of Medicinal Chemistry, American Chemical Society, 2015, 58 (16), pp.6559-6573. ⟨10.1021/acs.jmedchem.5b00991⟩. ⟨hal-01187307⟩

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