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|Ref Type||Journal Article|
|Authors||Fouqué A, Delalande O, Jean M, Castellano R, Josselin E, Malleter M, Shoji KF, Hung MD, Rampanarivo H, Collette Y, van de Weghe P, Legembre P|
|Title||A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells.|
|Journal||Journal of medicinal chemistry|
|Date||2015 Aug 27|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|DHM25||mTOR Inhibitor 51||DHM25 is an mTOR inhibitor that inhibits the activity of mTORC1 and mTORC2, potentially resulting in decreased tumor growth (PMID: 26237138).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA E545K||breast cancer||sensitive||DHM25||Preclinical - Cell culture||Actionable||In a preclinical study, DHM25 increased cell death in a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 26237138).||26237138|
|PIK3CA H1047R||breast cancer||sensitive||DHM25||Preclinical - Cell culture||Actionable||In a preclinical study, DHM25 increased cell death in breast cancer cell lines harboring PIK3CA H1047R in culture (PMID: 26237138).||26237138|
|PIK3CA K111N||breast cancer||sensitive||DHM25||Preclinical - Cell culture||Actionable||In a preclinical study, DHM25 increased cell death in a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 26237138).||26237138|