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

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.