Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo
Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a...
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| Veröffentlicht in: | Blood 2016-07, Vol.128 (3), p.410-414 |
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| creator | Kosciuczuk, Ewa M. Saleiro, Diana Kroczynska, Barbara Beauchamp, Elspeth M. Eckerdt, Frank Blyth, Gavin T. Abedin, Sameem M. Giles, Francis J. Altman, Jessica K. Platanias, Leonidas C. |
| description | Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a unique approach for the treatment of AML. We provide evidence for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E phosphorylation in AML cells and suppresses primitive leukemic progenitors from AML patients in vitro and in an AML xenograft model in vivo. Our findings provide evidence for potent preclinical antileukemic properties of merestinib and support its clinical development for the treatment of patients with AML.
•Merestinib blocks Mnk kinase activity in acute myeloid leukemia cells.•Merestinib suppresses human leukemic progenitors and exhibits potent antileukemic effects in a xenograft mouse model. |
| doi_str_mv | 10.1182/blood-2016-02-698704 |
| format | Article |
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•Merestinib blocks Mnk kinase activity in acute myeloid leukemia cells.•Merestinib suppresses human leukemic progenitors and exhibits potent antileukemic effects in a xenograft mouse model.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2016-02-698704</identifier><identifier>PMID: 27307295</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenosine Triphosphatases - antagonists & inhibitors ; Adenosine Triphosphatases - metabolism ; Animals ; Brief Report ; Cation Transport Proteins - antagonists & inhibitors ; Cation Transport Proteins - metabolism ; Cell Line, Tumor ; Copper-Transporting ATPases ; Enzyme Inhibitors - pharmacology ; Eukaryotic Initiation Factor-4E - metabolism ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - enzymology ; Mice ; Myeloid Neoplasia ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Blood, 2016-07, Vol.128 (3), p.410-414</ispartof><rights>2016 American Society of Hematology</rights><rights>2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-9915f0377d5ccdc5044ed83a83882bbdfdc5e3eb6507d725d11189878cb41ae93</citedby><cites>FETCH-LOGICAL-c463t-9915f0377d5ccdc5044ed83a83882bbdfdc5e3eb6507d725d11189878cb41ae93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27307295$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kosciuczuk, Ewa M.</creatorcontrib><creatorcontrib>Saleiro, Diana</creatorcontrib><creatorcontrib>Kroczynska, Barbara</creatorcontrib><creatorcontrib>Beauchamp, Elspeth M.</creatorcontrib><creatorcontrib>Eckerdt, Frank</creatorcontrib><creatorcontrib>Blyth, Gavin T.</creatorcontrib><creatorcontrib>Abedin, Sameem M.</creatorcontrib><creatorcontrib>Giles, Francis J.</creatorcontrib><creatorcontrib>Altman, Jessica K.</creatorcontrib><creatorcontrib>Platanias, Leonidas C.</creatorcontrib><title>Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo</title><title>Blood</title><addtitle>Blood</addtitle><description>Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a unique approach for the treatment of AML. We provide evidence for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E phosphorylation in AML cells and suppresses primitive leukemic progenitors from AML patients in vitro and in an AML xenograft model in vivo. Our findings provide evidence for potent preclinical antileukemic properties of merestinib and support its clinical development for the treatment of patients with AML.
•Merestinib blocks Mnk kinase activity in acute myeloid leukemia cells.•Merestinib suppresses human leukemic progenitors and exhibits potent antileukemic effects in a xenograft mouse model.</description><subject>Adenosine Triphosphatases - antagonists & inhibitors</subject><subject>Adenosine Triphosphatases - metabolism</subject><subject>Animals</subject><subject>Brief Report</subject><subject>Cation Transport Proteins - antagonists & inhibitors</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Copper-Transporting ATPases</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Eukaryotic Initiation Factor-4E - metabolism</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - enzymology</subject><subject>Mice</subject><subject>Myeloid Neoplasia</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUuPFCEUhYnROO3oPzCGpZtSnlXUxsRMfCUzcaNrQsGtmWtXQQvVHXvrL5d-OOrGFXA597twDiHPOXvFuRGvhyml0AjG24aJpu1Nx9QDsuJamIYxwR6SFWOsbVTf8QvypJRvjHElhX5MLkQnWSd6vSI_byBDWTDiQCvRrwu9iWu6xugKUOcX3OGypxjrfrsAnfcwJQx0gu0aZnR0k9MtRFxSLtTFQOHHHQ64HA4LnlWewjiCr8XKqbycjtLjYZeekkejmwo8O6-X5Ov7d1-uPjbXnz98unp73XjVyqXpe65HJrsuaO-D10wpCEY6I40RwxDGWgMJQ6tZFzqhA682VVeMHxR30MtL8ubE3WyHGYKHuGQ32U3G2eW9TQ7tvzcR7-xt2lnV6463sgJengE5fd9W1-yMxcM0uQhpWyw3rFVKatNWqTpJfU6lZBjvx3BmD_HZY3z2EJ9lwp7iq20v_n7ifdPvvP78AapRO4Rsi0eIHgLmarANCf8_4Rf8PbBb</recordid><startdate>20160721</startdate><enddate>20160721</enddate><creator>Kosciuczuk, Ewa M.</creator><creator>Saleiro, Diana</creator><creator>Kroczynska, Barbara</creator><creator>Beauchamp, Elspeth M.</creator><creator>Eckerdt, Frank</creator><creator>Blyth, Gavin T.</creator><creator>Abedin, Sameem M.</creator><creator>Giles, Francis J.</creator><creator>Altman, Jessica K.</creator><creator>Platanias, Leonidas C.</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160721</creationdate><title>Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo</title><author>Kosciuczuk, Ewa M. ; Saleiro, Diana ; Kroczynska, Barbara ; Beauchamp, Elspeth M. ; Eckerdt, Frank ; Blyth, Gavin T. ; Abedin, Sameem M. ; Giles, Francis J. ; Altman, Jessica K. ; Platanias, Leonidas C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-9915f0377d5ccdc5044ed83a83882bbdfdc5e3eb6507d725d11189878cb41ae93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adenosine Triphosphatases - antagonists & inhibitors</topic><topic>Adenosine Triphosphatases - metabolism</topic><topic>Animals</topic><topic>Brief Report</topic><topic>Cation Transport Proteins - antagonists & inhibitors</topic><topic>Cation Transport Proteins - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Copper-Transporting ATPases</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Eukaryotic Initiation Factor-4E - metabolism</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - enzymology</topic><topic>Mice</topic><topic>Myeloid Neoplasia</topic><topic>Neoplasm Proteins - antagonists & inhibitors</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kosciuczuk, Ewa M.</creatorcontrib><creatorcontrib>Saleiro, Diana</creatorcontrib><creatorcontrib>Kroczynska, Barbara</creatorcontrib><creatorcontrib>Beauchamp, Elspeth M.</creatorcontrib><creatorcontrib>Eckerdt, Frank</creatorcontrib><creatorcontrib>Blyth, Gavin T.</creatorcontrib><creatorcontrib>Abedin, Sameem M.</creatorcontrib><creatorcontrib>Giles, Francis J.</creatorcontrib><creatorcontrib>Altman, Jessica K.</creatorcontrib><creatorcontrib>Platanias, Leonidas C.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kosciuczuk, Ewa M.</au><au>Saleiro, Diana</au><au>Kroczynska, Barbara</au><au>Beauchamp, Elspeth M.</au><au>Eckerdt, Frank</au><au>Blyth, Gavin T.</au><au>Abedin, Sameem M.</au><au>Giles, Francis J.</au><au>Altman, Jessica K.</au><au>Platanias, Leonidas C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2016-07-21</date><risdate>2016</risdate><volume>128</volume><issue>3</issue><spage>410</spage><epage>414</epage><pages>410-414</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a unique approach for the treatment of AML. We provide evidence for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E phosphorylation in AML cells and suppresses primitive leukemic progenitors from AML patients in vitro and in an AML xenograft model in vivo. Our findings provide evidence for potent preclinical antileukemic properties of merestinib and support its clinical development for the treatment of patients with AML.
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| subjects | Adenosine Triphosphatases - antagonists & inhibitors Adenosine Triphosphatases - metabolism Animals Brief Report Cation Transport Proteins - antagonists & inhibitors Cation Transport Proteins - metabolism Cell Line, Tumor Copper-Transporting ATPases Enzyme Inhibitors - pharmacology Eukaryotic Initiation Factor-4E - metabolism Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - enzymology Mice Myeloid Neoplasia Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - metabolism Xenograft Model Antitumor Assays |
| title | Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo |
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