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
  • 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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