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DHM25, a new Covalent mTOR Inhibitor

Published on August 11th, 2015 by Patrick Legembre

DHM25, A novel Covalent mTOR Inhibitor

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

  • Amélie Fouqué, Olivier Delalande, Mickael Jean, Rémy Castellano, Emmanuelle Josselin, Marine Malleter, Kenji F. Shoji, Mac Dinh Hung, Hariniaina Rampanarivo, Yves Collette, Pierre van de Weghe*, and Patrick Legembre*
  • J. Med. Chem., Article ASAP
  • DOI: 10.1021/acs.jmedchem.5b00991
  • Publication Date (Web): August 3, 2015
  • Copyright © 2015 American Chemical Society
  • *Phone: (+33)-2-2323-3803. Fax: (+33)-2-2323-4425. E-mail: pierre.van-de-weghe@univ-rennes1.fr.
  • *Phone: (+33)-2-2323-7241. Fax: (+33)-2-9925-3164. E-mail: patrick.legembre@inserm.fr.

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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