A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma
The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-di...
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| Veröffentlicht in: | Blood 2010-01, Vol.115 (4), p.824-833 |
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| creator | Lin, Ying-Wei Beharry, Zanna M. Hill, Elizabeth G. Song, Jin H. Wang, Wenxue Xia, Zuping Zhang, Zhenhua Aplan, Peter D. Aster, Jon C. Smith, Charles D. Kraft, Andrew S. |
| description | The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre–T-LBL/T-ALL) being highly sensitive. Incubation of pre–T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre–T-LBL cells. In immunodeficient mice carrying subcutaneous pre–T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre–T-LBL. |
| doi_str_mv | 10.1182/blood-2009-07-233445 |
| format | Article |
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We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre–T-LBL/T-ALL) being highly sensitive. Incubation of pre–T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre–T-LBL cells. In immunodeficient mice carrying subcutaneous pre–T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre–T-LBL.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2009-07-233445</identifier><identifier>PMID: 19965690</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Animals ; Apoptosis - drug effects ; Benzylidene Compounds - pharmacology ; Biological and medical sciences ; Cell Division - drug effects ; Cell Line, Tumor ; Extracellular Signal-Regulated MAP Kinases - metabolism ; G1 Phase - drug effects ; Hematologic and hematopoietic diseases ; Humans ; Intracellular Signaling Peptides and Proteins - metabolism ; Jurkat Cells ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphoid Neoplasia ; MAP Kinase Signaling System - drug effects ; Medical sciences ; Mice ; Mice, Knockout ; Mice, Transgenic ; Phosphorylation - drug effects ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors ; Proto-Oncogene Proteins c-pim-1 - genetics ; Proto-Oncogene Proteins c-pim-1 - metabolism ; Thiazolidinediones - pharmacology ; TOR Serine-Threonine Kinases</subject><ispartof>Blood, 2010-01, Vol.115 (4), p.824-833</ispartof><rights>2010 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><rights>2010 by The American Society of Hematology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c492t-13de8dadd652a4d96039177426fdb0524439b6c4465f68fb42a05f0ed4e37ba73</citedby><cites>FETCH-LOGICAL-c492t-13de8dadd652a4d96039177426fdb0524439b6c4465f68fb42a05f0ed4e37ba73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22364386$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19965690$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Ying-Wei</creatorcontrib><creatorcontrib>Beharry, Zanna M.</creatorcontrib><creatorcontrib>Hill, Elizabeth G.</creatorcontrib><creatorcontrib>Song, Jin H.</creatorcontrib><creatorcontrib>Wang, Wenxue</creatorcontrib><creatorcontrib>Xia, Zuping</creatorcontrib><creatorcontrib>Zhang, Zhenhua</creatorcontrib><creatorcontrib>Aplan, Peter D.</creatorcontrib><creatorcontrib>Aster, Jon C.</creatorcontrib><creatorcontrib>Smith, Charles D.</creatorcontrib><creatorcontrib>Kraft, Andrew S.</creatorcontrib><title>A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma</title><title>Blood</title><addtitle>Blood</addtitle><description>The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre–T-LBL/T-ALL) being highly sensitive. Incubation of pre–T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre–T-LBL cells. In immunodeficient mice carrying subcutaneous pre–T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre–T-LBL.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Benzylidene Compounds - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Division - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>G1 Phase - drug effects</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Jurkat Cells</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphoid Neoplasia</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Phosphorylation - drug effects</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-pim-1 - genetics</subject><subject>Proto-Oncogene Proteins c-pim-1 - metabolism</subject><subject>Thiazolidinediones - pharmacology</subject><subject>TOR Serine-Threonine Kinases</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtr3DAUhUVpaaZJ_kEp2nTp5uph2doUQugLAu0iXQtZuo7VkS0jeRLy7-vJDEm7yUogne_cq3MIec_gE2Mtv-hiSr7iALqCpuJCSFm_IhtW87YC4PCabABAVVI37IS8K-UPAJOC12_JCdNa1UrDhtxf0jLaGOmYIrpdRBqmIXRhSZmmnv4KI51zWjBMdBsmW7DQdbDbFroMSG9zul-GvXDOK53LSt1UDle_-DDOQ-qiLUtwNOJui2OwF4fr0Z6RN72NBc-P5yn5_fXLzdX36vrntx9Xl9eVk5ovFRMeW2-9VzW30msFQrOmkVz1voOaSyl0p5yUqu5V23eSW6h7QC9RNJ1txCn5fPCdd92I3uG0ZBvNnMNo84NJNpj_X6YwmNt0Z7iW-5RWA3kwcDmVkrF_YhmYfRHmsQizL8JAYw5FrNiHf-c-Q8fkV8HHo8AWZ2Of7eRCedJxLpQUrXr-AK4p3QXMpriAk0Mf1sgX41N4eZO_b-Oq2w</recordid><startdate>20100128</startdate><enddate>20100128</enddate><creator>Lin, Ying-Wei</creator><creator>Beharry, Zanna M.</creator><creator>Hill, Elizabeth G.</creator><creator>Song, Jin H.</creator><creator>Wang, Wenxue</creator><creator>Xia, Zuping</creator><creator>Zhang, Zhenhua</creator><creator>Aplan, Peter D.</creator><creator>Aster, Jon C.</creator><creator>Smith, Charles D.</creator><creator>Kraft, Andrew S.</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20100128</creationdate><title>A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma</title><author>Lin, Ying-Wei ; Beharry, Zanna M. ; Hill, Elizabeth G. ; Song, Jin H. ; Wang, Wenxue ; Xia, Zuping ; Zhang, Zhenhua ; Aplan, Peter D. ; Aster, Jon C. ; Smith, Charles D. ; Kraft, Andrew S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c492t-13de8dadd652a4d96039177426fdb0524439b6c4465f68fb42a05f0ed4e37ba73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Benzylidene Compounds - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Division - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>G1 Phase - drug effects</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Jurkat Cells</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Lymphoid Neoplasia</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Phosphorylation - drug effects</topic><topic>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</topic><topic>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-pim-1 - genetics</topic><topic>Proto-Oncogene Proteins c-pim-1 - metabolism</topic><topic>Thiazolidinediones - pharmacology</topic><topic>TOR Serine-Threonine Kinases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Ying-Wei</creatorcontrib><creatorcontrib>Beharry, Zanna M.</creatorcontrib><creatorcontrib>Hill, Elizabeth G.</creatorcontrib><creatorcontrib>Song, Jin H.</creatorcontrib><creatorcontrib>Wang, Wenxue</creatorcontrib><creatorcontrib>Xia, Zuping</creatorcontrib><creatorcontrib>Zhang, Zhenhua</creatorcontrib><creatorcontrib>Aplan, Peter D.</creatorcontrib><creatorcontrib>Aster, Jon C.</creatorcontrib><creatorcontrib>Smith, Charles D.</creatorcontrib><creatorcontrib>Kraft, Andrew S.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Ying-Wei</au><au>Beharry, Zanna M.</au><au>Hill, Elizabeth G.</au><au>Song, Jin H.</au><au>Wang, Wenxue</au><au>Xia, Zuping</au><au>Zhang, Zhenhua</au><au>Aplan, Peter D.</au><au>Aster, Jon C.</au><au>Smith, Charles D.</au><au>Kraft, Andrew S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2010-01-28</date><risdate>2010</risdate><volume>115</volume><issue>4</issue><spage>824</spage><epage>833</epage><pages>824-833</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre–T-LBL/T-ALL) being highly sensitive. Incubation of pre–T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre–T-LBL cells. In immunodeficient mice carrying subcutaneous pre–T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre–T-LBL.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>19965690</pmid><doi>10.1182/blood-2009-07-233445</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis - drug effects Benzylidene Compounds - pharmacology Biological and medical sciences Cell Division - drug effects Cell Line, Tumor Extracellular Signal-Regulated MAP Kinases - metabolism G1 Phase - drug effects Hematologic and hematopoietic diseases Humans Intracellular Signaling Peptides and Proteins - metabolism Jurkat Cells Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoid Neoplasia MAP Kinase Signaling System - drug effects Medical sciences Mice Mice, Knockout Mice, Transgenic Phosphorylation - drug effects Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors Proto-Oncogene Proteins c-pim-1 - genetics Proto-Oncogene Proteins c-pim-1 - metabolism Thiazolidinediones - pharmacology TOR Serine-Threonine Kinases |
| title | A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma |
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