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

作者：Fouque Amelie; Delalande Olivier; Jean Mickael; Castellano Remy; Josselin Emmanuelle; Malleter Marine; Shoji Kenji F; Mac Dinh Hung; Rampanarivo Hariniaina; Collette Yves; van de Weghe Pierre^*; Legembre Patrick

来源：Journal of Medicinal Chemistry, 2015, 58(16): 6559-6573.

DOI：10.1021/acs.jmedchem.5b00991

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.

• 出版日期2015-8-27