Reference Detail

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
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
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
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 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 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