2. Academic Validation
  3. A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells

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

  • J Med Chem. 2015 Aug 27;58(16):6559-73. doi: 10.1021/acs.jmedchem.5b00991.
Amélie Fouqué 1 2 3,  Olivier Delalande 1 4,  Mickael Jean 1 5,  Rémy Castellano 6,  Emmanuelle Josselin 6,  Marine Malleter 1,  Kenji F Shoji 1 7,  Mac Dinh Hung 8,  Hariniaina Rampanarivo 1 2 3 4,  Yves Collette 6,  Pierre van de Weghe 1 5,  Patrick Legembre 1 2 3
Affiliations

Affiliations

  • 1 Université de Rennes-1 , 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.
  • 2 CLCC Eugène Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, rue bataille Flandres Dunkerque, 35042 Rennes, France.
  • 3 Equipe Labellisée Ligue Contre le Cancer, rue bataille Flandres Dunkerque, Rennes, France.
  • 4 IGDR, CNRS UMR 6290, UFR des Sciences Biologiques et Pharmaceutiques, 2 Av. du Professeur Léon Bernard, 35043 Rennes, France.
  • 5 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.
  • 6 CRCM, INSERM, U1068; Institut Paoli-Calmettes; Aix-Marseille Université; CNRS, UMR 7258, Marseille, France.
  • 7 INSERM, U1085, 2 avenue du Prof. Leon Bernard, 35043 Rennes, France.
  • 8 Faculty of Chemistry, National Vietnam University , 19 Le Thanh Tong, Hanoi, Vietnam.
PMID: 26237138 DOI: 10.1021/acs.jmedchem.5b00991
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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