Identification of novel FLT3 kinase inhibitors
FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia. Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial rem...
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| Veröffentlicht in: | European journal of medicinal chemistry 2013-05, Vol.63, p.713-721 |
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| container_title | European journal of medicinal chemistry |
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| creator | Pauwels, Daphnie Klaassen, Hugo Lahortiga, Idoya Kilonda, Amuri Jacobs, Kris Sweron, Bram Corbau, Romuald Chaltin, Patrick Marchand, Arnaud Cools, Jan |
| description | FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia. Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial remission and development of resistance has been reported. In this work we describe the identification of potent and novel dual FLT3/PDGFR inhibitors that resulted from our efforts to screen a library of 25,607 small molecules against the FLT3 dependent cell line MOLM-13 and the PDGFR dependent cell line EOL-1. This effort led to the identification of five compounds that were confirmed to be active on additional FLT3 dependent cell lines (cellular EC50 values between 35 and 700 nM), while having no significant effect on 24 other tyrosine kinases.
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•We identified five potent and novel dual FLT3/PDGFR inhibitors in a cell based screening.•We confirmed direct inhibition of the autophosphorylation of the oncogenic FLT3-ITD and FIP1L1-PDGFRα by western blotting.•The inhibitors appeared to be selective for FLT3/PDGFR, because we observed no effect on 24 other kinases.•Some inhibitors showed a slight inhibitory effect on the resistant FLT3 mutants. |
| doi_str_mv | 10.1016/j.ejmech.2013.03.024 |
| format | Article |
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[Display omitted]
•We identified five potent and novel dual FLT3/PDGFR inhibitors in a cell based screening.•We confirmed direct inhibition of the autophosphorylation of the oncogenic FLT3-ITD and FIP1L1-PDGFRα by western blotting.•The inhibitors appeared to be selective for FLT3/PDGFR, because we observed no effect on 24 other kinases.•Some inhibitors showed a slight inhibitory effect on the resistant FLT3 mutants.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2013.03.024</identifier><identifier>PMID: 23567961</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Acute myeloid leukemia ; Blotting, Western ; Cell based drug screening ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; FLT3 ; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors ; fms-Like Tyrosine Kinase 3 - metabolism ; Humans ; Hypereosinophilic Syndrome - metabolism ; Hypereosinophilic Syndrome - pathology ; Inhibitors ; Leukemia, Monocytic, Acute - metabolism ; Leukemia, Monocytic, Acute - pathology ; Molecular Structure ; PDGFR ; Phosphorylation - drug effects ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors ; Receptor, Platelet-Derived Growth Factor alpha - metabolism ; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors ; Receptor, Platelet-Derived Growth Factor beta - metabolism ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Structure-Activity Relationship ; Tyrosine kinase</subject><ispartof>European journal of medicinal chemistry, 2013-05, Vol.63, p.713-721</ispartof><rights>2013 Elsevier Masson SAS</rights><rights>Copyright © 2013 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-3f2df1ed87825d5137fa2b5cd35cf829078406e4f01f6644a057cb1a7ed976673</citedby><cites>FETCH-LOGICAL-c362t-3f2df1ed87825d5137fa2b5cd35cf829078406e4f01f6644a057cb1a7ed976673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523413001724$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23567961$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pauwels, Daphnie</creatorcontrib><creatorcontrib>Klaassen, Hugo</creatorcontrib><creatorcontrib>Lahortiga, Idoya</creatorcontrib><creatorcontrib>Kilonda, Amuri</creatorcontrib><creatorcontrib>Jacobs, Kris</creatorcontrib><creatorcontrib>Sweron, Bram</creatorcontrib><creatorcontrib>Corbau, Romuald</creatorcontrib><creatorcontrib>Chaltin, Patrick</creatorcontrib><creatorcontrib>Marchand, Arnaud</creatorcontrib><creatorcontrib>Cools, Jan</creatorcontrib><title>Identification of novel FLT3 kinase inhibitors</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia. Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial remission and development of resistance has been reported. In this work we describe the identification of potent and novel dual FLT3/PDGFR inhibitors that resulted from our efforts to screen a library of 25,607 small molecules against the FLT3 dependent cell line MOLM-13 and the PDGFR dependent cell line EOL-1. This effort led to the identification of five compounds that were confirmed to be active on additional FLT3 dependent cell lines (cellular EC50 values between 35 and 700 nM), while having no significant effect on 24 other tyrosine kinases.
[Display omitted]
•We identified five potent and novel dual FLT3/PDGFR inhibitors in a cell based screening.•We confirmed direct inhibition of the autophosphorylation of the oncogenic FLT3-ITD and FIP1L1-PDGFRα by western blotting.•The inhibitors appeared to be selective for FLT3/PDGFR, because we observed no effect on 24 other kinases.•Some inhibitors showed a slight inhibitory effect on the resistant FLT3 mutants.</description><subject>Acute myeloid leukemia</subject><subject>Blotting, Western</subject><subject>Cell based drug screening</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>FLT3</subject><subject>fms-Like Tyrosine Kinase 3 - antagonists & inhibitors</subject><subject>fms-Like Tyrosine Kinase 3 - metabolism</subject><subject>Humans</subject><subject>Hypereosinophilic Syndrome - metabolism</subject><subject>Hypereosinophilic Syndrome - pathology</subject><subject>Inhibitors</subject><subject>Leukemia, Monocytic, Acute - metabolism</subject><subject>Leukemia, Monocytic, Acute - pathology</subject><subject>Molecular Structure</subject><subject>PDGFR</subject><subject>Phosphorylation - drug effects</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors</subject><subject>Receptor, Platelet-Derived Growth Factor alpha - metabolism</subject><subject>Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors</subject><subject>Receptor, Platelet-Derived Growth Factor beta - metabolism</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tyrosine kinase</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1Lw0AQhhdRbK3-A5EcvSTOfqcXQcRqoeClnpdkd5ZubJKaTQv-e1NSPQoDc3neeZmHkFsKGQWqHqoMqxrtJmNAeQbDMHFGplSrPOVMinMyBcZ4KhkXE3IVYwUAUgFckgnjUum5olOSLR02ffDBFn1om6T1SdMecJssVmuefIamiJiEZhPK0LddvCYXvthGvDntGflYvKyf39LV--vy-WmVWq5Yn3LPnKfocp0z6STl2heslNZxaX3O5qBzAQqFB-qVEqIAqW1JC41urpXSfEbux7u7rv3aY-xNHaLF7bZosN1HQ7mSIJmQYkDFiNqujbFDb3ZdqIvu21AwR1OmMqMpczRlYBh2jN2dGvZlje4v9KtmAB5HAIc_DwE7E23AxqILHdreuDb83_ADLal5hw</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Pauwels, Daphnie</creator><creator>Klaassen, Hugo</creator><creator>Lahortiga, Idoya</creator><creator>Kilonda, Amuri</creator><creator>Jacobs, Kris</creator><creator>Sweron, Bram</creator><creator>Corbau, Romuald</creator><creator>Chaltin, Patrick</creator><creator>Marchand, Arnaud</creator><creator>Cools, Jan</creator><general>Elsevier Masson SAS</general><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></search><sort><creationdate>20130501</creationdate><title>Identification of novel FLT3 kinase inhibitors</title><author>Pauwels, Daphnie ; Klaassen, Hugo ; Lahortiga, Idoya ; Kilonda, Amuri ; Jacobs, Kris ; Sweron, Bram ; Corbau, Romuald ; Chaltin, Patrick ; Marchand, Arnaud ; Cools, Jan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-3f2df1ed87825d5137fa2b5cd35cf829078406e4f01f6644a057cb1a7ed976673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acute myeloid leukemia</topic><topic>Blotting, Western</topic><topic>Cell based drug screening</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>FLT3</topic><topic>fms-Like Tyrosine Kinase 3 - antagonists & inhibitors</topic><topic>fms-Like Tyrosine Kinase 3 - metabolism</topic><topic>Humans</topic><topic>Hypereosinophilic Syndrome - metabolism</topic><topic>Hypereosinophilic Syndrome - pathology</topic><topic>Inhibitors</topic><topic>Leukemia, Monocytic, Acute - metabolism</topic><topic>Leukemia, Monocytic, Acute - pathology</topic><topic>Molecular Structure</topic><topic>PDGFR</topic><topic>Phosphorylation - drug effects</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors</topic><topic>Receptor, Platelet-Derived Growth Factor alpha - metabolism</topic><topic>Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors</topic><topic>Receptor, Platelet-Derived Growth Factor beta - metabolism</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Tyrosine kinase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pauwels, Daphnie</creatorcontrib><creatorcontrib>Klaassen, Hugo</creatorcontrib><creatorcontrib>Lahortiga, Idoya</creatorcontrib><creatorcontrib>Kilonda, Amuri</creatorcontrib><creatorcontrib>Jacobs, Kris</creatorcontrib><creatorcontrib>Sweron, Bram</creatorcontrib><creatorcontrib>Corbau, Romuald</creatorcontrib><creatorcontrib>Chaltin, Patrick</creatorcontrib><creatorcontrib>Marchand, Arnaud</creatorcontrib><creatorcontrib>Cools, Jan</creatorcontrib><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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pauwels, Daphnie</au><au>Klaassen, Hugo</au><au>Lahortiga, Idoya</au><au>Kilonda, Amuri</au><au>Jacobs, Kris</au><au>Sweron, Bram</au><au>Corbau, Romuald</au><au>Chaltin, Patrick</au><au>Marchand, Arnaud</au><au>Cools, Jan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of novel FLT3 kinase inhibitors</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>63</volume><spage>713</spage><epage>721</epage><pages>713-721</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia. Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial remission and development of resistance has been reported. In this work we describe the identification of potent and novel dual FLT3/PDGFR inhibitors that resulted from our efforts to screen a library of 25,607 small molecules against the FLT3 dependent cell line MOLM-13 and the PDGFR dependent cell line EOL-1. This effort led to the identification of five compounds that were confirmed to be active on additional FLT3 dependent cell lines (cellular EC50 values between 35 and 700 nM), while having no significant effect on 24 other tyrosine kinases.
[Display omitted]
•We identified five potent and novel dual FLT3/PDGFR inhibitors in a cell based screening.•We confirmed direct inhibition of the autophosphorylation of the oncogenic FLT3-ITD and FIP1L1-PDGFRα by western blotting.•The inhibitors appeared to be selective for FLT3/PDGFR, because we observed no effect on 24 other kinases.•Some inhibitors showed a slight inhibitory effect on the resistant FLT3 mutants.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>23567961</pmid><doi>10.1016/j.ejmech.2013.03.024</doi><tpages>9</tpages></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2013-05, Vol.63, p.713-721 |
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| subjects | Acute myeloid leukemia Blotting, Western Cell based drug screening Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Dose-Response Relationship, Drug Drug Screening Assays, Antitumor FLT3 fms-Like Tyrosine Kinase 3 - antagonists & inhibitors fms-Like Tyrosine Kinase 3 - metabolism Humans Hypereosinophilic Syndrome - metabolism Hypereosinophilic Syndrome - pathology Inhibitors Leukemia, Monocytic, Acute - metabolism Leukemia, Monocytic, Acute - pathology Molecular Structure PDGFR Phosphorylation - drug effects Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors Receptor, Platelet-Derived Growth Factor alpha - metabolism Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors Receptor, Platelet-Derived Growth Factor beta - metabolism Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship Tyrosine kinase |
| title | Identification of novel FLT3 kinase inhibitors |
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