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10.1038/leu.2015.105 http://scihub22266oqcxt.onion/10.1038/leu.2015.105 C4558374!4558374 !25917267     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25917267 &cmd=llinks): Failed to open stream: HTTP request failed! 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The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL |pdf=|usr=}}{{25917267 }} gab.com Text The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL JO: Leukemia http://www.kidney.de/pget.php?&tw=1&pmid=25917267 #FOAvip The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110? with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110? and p110? in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110? and p110? isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36?nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1??M IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes. Twit Text FOAVip The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL ????Leukemia http://www.kidney.de/pget.php?&tw=1&pmid=25917267 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25917267 #FOAvip English Wikipedia <ref>{{Cite pmid|25917267 }}</ref> The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL #MMPMID25917267 Balakrishnan K ; Peluso M ; Fu M ; Rosin NY ; Burger JA ; Wierda WG ; Keating MJ ; Faia K ; O'Brien S ; Kutok JL ; Gandhi V Leukemia 2015[Sep]; 29 (9 ): 1811-22 PMID25917267 show ga The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110? with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110? and p110? in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110? and p110? isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36?nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1??M IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes. |*Phosphoinositide-3 Kinase Inhibitors [MESH] |Adenine/analogs & derivatives [MESH] |Aged [MESH] |Aged, 80 and over [MESH] |Apoptosis/*drug effects [MESH] |Bone Marrow Cells/metabolism [MESH] |Case-Control Studies [MESH] |Cell Proliferation/drug effects [MESH] |Cell Survival/drug effects/immunology [MESH] |Chemokine CCL3/metabolism [MESH] |Chemokine CCL4/metabolism [MESH] |Chemotaxis/drug effects/immunology [MESH] |Female [MESH] |Humans [MESH] |Isoquinolines/*pharmacology [MESH] |Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/genetics/*metabolism [MESH] |Leukocytes, Mononuclear/drug effects/metabolism [MESH] |Male [MESH] |Middle Aged [MESH] |Phosphatidylinositol 3-Kinases/*metabolism [MESH] |Phosphorylation [MESH] |Piperidines [MESH] |Prognosis [MESH] |Proto-Oncogene Proteins c-akt/*metabolism [MESH] |Purines/*pharmacology [MESH] |Pyrazoles/pharmacology [MESH] |Pyrimidines/pharmacology [MESH] |Quinazolinones/pharmacology [MESH] |Receptors, Antigen, B-Cell/metabolism [MESH] |Ribosomal Protein S6 Kinases/*metabolism [MESH] |Signal Transduction/*drug effects [MESH]The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-14(epmc).pdf DeepDyve Pubget Overpricing