title: 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.
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.|CLCC Eugène Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, rue bataille Flandres Dunkerque, 35042 Rennes, France.|Equipe Labellisée Ligue Contre le Cancer, rue bataille Flandres Dunkerque, Rennes, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Fouqué
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.|IGDR, CNRS UMR 6290, UFR des Sciences Biologiques et Pharmaceutiques, 2 Av. du Professeur Léon Bernard, 35043 Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delalande
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.|UMR6226, CNRS, Institut des Sciences Chimiques de Rennes, Equipe Produits Naturels, Synthèses, Chimie Médicinale, UFR des Sciences Biologiques et Pharmaceutiques, 2 Av. du Professeur Léon Bernard, 35043 Rennes, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Jean
authors.affiliation: CRCM, INSERM, U1068; Institut Paoli-Calmettes; Aix-Marseille Université; CNRS, UMR 7258, Marseille, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.affiliation: CRCM, INSERM, U1068; Institut Paoli-Calmettes; Aix-Marseille Université; CNRS, UMR 7258, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Josselin
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Malleter
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.|INSERM, U1085, 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Shoji
authors.affiliation: Faculty of Chemistry, National Vietnam University , 19 Le Thanh Tong, Hanoi, Vietnam.
authors.forename: Mac Dinh
authors.initials: MD
authors.lastname: Hung
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.|CLCC Eugène Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, rue bataille Flandres Dunkerque, 35042 Rennes, France.|Equipe Labellisée Ligue Contre le Cancer, rue bataille Flandres Dunkerque, Rennes, France.|IGDR, CNRS UMR 6290, UFR des Sciences Biologiques et Pharmaceutiques, 2 Av. du Professeur Léon Bernard, 35043 Rennes, France.
authors.forename: Hariniaina
authors.initials: H
authors.lastname: Rampanarivo
authors.affiliation: CRCM, INSERM, U1068; Institut Paoli-Calmettes; Aix-Marseille Université; CNRS, UMR 7258, Marseille, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.|UMR6226, CNRS, Institut des Sciences Chimiques de Rennes, Equipe Produits Naturels, Synthèses, Chimie Médicinale, UFR des Sciences Biologiques et Pharmaceutiques, 2 Av. du Professeur Léon Bernard, 35043 Rennes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: van de Weghe
authors.affiliation: Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.|CLCC Eugène Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, rue bataille Flandres Dunkerque, 35042 Rennes, France.|Equipe Labellisée Ligue Contre le Cancer, rue bataille Flandres Dunkerque, Rennes, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Legembre
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D051058:Oncogene Protein v-akt / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000602648:6,8-dibromo-2-(4-bromophenyl)-3-nitro-2H-chromene; D000970:Antineoplastic Agents; D001578:Benzopyrans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases