The phosphoinositide-3-kinase
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[delta] with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The...
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| Veröffentlicht in: | Leukemia 2015-09, Vol.29 (9), p.1811 |
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| creator | Peluso, M Wierda, W G Balakrishnan, K Burger, J A Fu, M Rosin, N Y Keating, M J |
| description | 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[delta] with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110[delta] and p110[gamma] in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110[delta] and p110[gamma] isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P |
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Inhibition of p110[delta] with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110[delta] and p110[gamma] in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110[delta] and p110[gamma] 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 IC.sub.50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT.sup.Ser473 is observed with an IC.sub.50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 [mu]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.sup.Ser473, BAD.sup.Ser112, ERK.sup.Thr202/Tyr204 and S6.sup.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.</description><identifier>ISSN: 0887-6924</identifier><language>eng</language><publisher>Nature Publishing Group</publisher><subject>Care and treatment ; Cell receptors ; Chronic lymphocytic leukemia ; Development and progression ; Genetic aspects ; Health aspects ; Phosphotransferases</subject><ispartof>Leukemia, 2015-09, Vol.29 (9), p.1811</ispartof><rights>COPYRIGHT 2015 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids></links><search><creatorcontrib>Peluso, M</creatorcontrib><creatorcontrib>Wierda, W G</creatorcontrib><creatorcontrib>Balakrishnan, K</creatorcontrib><creatorcontrib>Burger, J A</creatorcontrib><creatorcontrib>Fu, M</creatorcontrib><creatorcontrib>Rosin, N Y</creatorcontrib><creatorcontrib>Keating, M J</creatorcontrib><title>The phosphoinositide-3-kinase</title><title>Leukemia</title><description>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[delta] with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110[delta] and p110[gamma] in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110[delta] and p110[gamma] 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 IC.sub.50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT.sup.Ser473 is observed with an IC.sub.50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 [mu]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.sup.Ser473, BAD.sup.Ser112, ERK.sup.Thr202/Tyr204 and S6.sup.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.</description><subject>Care and treatment</subject><subject>Cell receptors</subject><subject>Chronic lymphocytic leukemia</subject><subject>Development and progression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Phosphotransferases</subject><issn>0887-6924</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNpjYeA0sLAw1zWzNDLhYOAqLs4yMDA0MTcz42SQDclIVSjIyC8G4sy8_OLMksyUVF1j3ezMvMTiVB4G1rTEnOJUXijNzaDm5hri7KGbnpiTGp-RmphTklGcn1NakpmfVxzvaGZoYGRgYmJgZEy0QgAqBC2a</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Peluso, M</creator><creator>Wierda, W G</creator><creator>Balakrishnan, K</creator><creator>Burger, J A</creator><creator>Fu, M</creator><creator>Rosin, N Y</creator><creator>Keating, M J</creator><general>Nature Publishing Group</general><scope/></search><sort><creationdate>20150901</creationdate><title>The phosphoinositide-3-kinase</title><author>Peluso, M ; Wierda, W G ; Balakrishnan, K ; Burger, J A ; Fu, M ; Rosin, N Y ; Keating, M J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-gale_healthsolutions_A6102044023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Care and treatment</topic><topic>Cell receptors</topic><topic>Chronic lymphocytic leukemia</topic><topic>Development and progression</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Phosphotransferases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Peluso, M</creatorcontrib><creatorcontrib>Wierda, W G</creatorcontrib><creatorcontrib>Balakrishnan, K</creatorcontrib><creatorcontrib>Burger, J A</creatorcontrib><creatorcontrib>Fu, M</creatorcontrib><creatorcontrib>Rosin, N Y</creatorcontrib><creatorcontrib>Keating, M J</creatorcontrib><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Peluso, M</au><au>Wierda, W G</au><au>Balakrishnan, K</au><au>Burger, J A</au><au>Fu, M</au><au>Rosin, N Y</au><au>Keating, M J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The phosphoinositide-3-kinase</atitle><jtitle>Leukemia</jtitle><date>2015-09-01</date><risdate>2015</risdate><volume>29</volume><issue>9</issue><spage>1811</spage><pages>1811-</pages><issn>0887-6924</issn><abstract>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[delta] with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110[delta] and p110[gamma] in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110[delta] and p110[gamma] 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 IC.sub.50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT.sup.Ser473 is observed with an IC.sub.50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. 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| source | Nature; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Care and treatment Cell receptors Chronic lymphocytic leukemia Development and progression Genetic aspects Health aspects Phosphotransferases |
| title | The phosphoinositide-3-kinase |
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