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Ref Type Journal Article
PMID (26237138)
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 Vol Issue Date Pages Journal Short Title
Journal of medicinal chemistry 58 16 2015 Aug 27 6559-73 J Med Chem
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
DHM25 DHM25 6 0
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 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
PTEN L108R breast cancer sensitive DHM25 Preclinical - Cell culture Actionable In a preclinical study, DHM25 increased cell death in a breast cancer cell line harboring PTEN L108R 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
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
PTEN A72fs triple-receptor negative breast cancer sensitive DHM25 Preclinical - Cell culture Actionable In a preclinical study, DHM25 increased cell death in a triple-negative breast cancer cell line harboring PTEN A72fs*5 in culture (PMID: 26237138). 26237138
PTEN V275* triple-receptor negative breast cancer sensitive DHM25 Preclinical - Cell culture Actionable In a preclinical study, DHM25 increased cell death and decreased migration of a triple-negative breast cancer cell line harboring PTEN V275* in culture (PMID: 26237138). 26237138