Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
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
ISSN: 0022-2623

hal-01187307
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187307
DOI : 10.1021/acs.jmedchem.5b00991
PUBMED : 26237138

Éditeur(s) : HAL CCSD Springer Verlag (Germany)
Résumé : International audience
Tight control of basal cytosolic Ca(2+) concentration is essential for cell survival and to fine-tune Ca(2+)-dependent cell functions. A way to control this basal cytosolic Ca(2+) concentration is to regulate membrane Ca(2+) channels including store-operated Ca(2+) channels and secondary messenger-operated channels linked to G-protein-coupled or tyrosine kinase receptor activation. Orai, with or without its reticular STIM partner and Transient Receptor Potential (TRP) proteins, were considered to be the main Ca(2+) channels involved. It is well accepted that, in response to cell stimulation, opening of these Ca(2+) channels contributes to Ca(2+) entry and the transient increase in cytosolic Ca(2+) concentration involved in intracellular signaling. However, in various experimental conditions, Ca(2+) entry and/or Ca(2+) currents can be recorded at rest, without application of any experimental stimulation. This led to the proposition that some plasma membrane Ca(2+) channels are already open/activated in basal condition, contributing therefore to constitutive Ca(2+) entry. This article focuses on direct and indirect observations supporting constitutive activity of channels belonging to the Orai and TRP families and on the mechanisms underlying their basal/constitutive activities.
ISSN: 0175-7571

hal-01528591
https://hal.archives-ouvertes.fr/hal-01528591
DOI : 10.1007/s00249-017-1216-8
PUBMED : 28516266