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Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase
A novel class of pyridone-based inhibitors of Pim-1 kinase is reported. A complex crystal structure of Pim-1/compound 1 (IC 50 of 1 = 50 nM) defined an inhibitory mechanism of action. A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements f...
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| Published in: | Bioorganic & medicinal chemistry letters 2007-03, Vol.17 (6), p.1679-1683 |
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| Main Authors: | , , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c481t-643271e1005a507e192b76e13373bc774208dcf28faa352ffe977d94afad17ef3 |
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| cites | cdi_FETCH-LOGICAL-c481t-643271e1005a507e192b76e13373bc774208dcf28faa352ffe977d94afad17ef3 |
| container_end_page | 1683 |
| container_issue | 6 |
| container_start_page | 1679 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 17 |
| creator | Cheney, I. Wayne Yan, Shunqi Appleby, Todd Walker, Heli Vo, Todd Yao, Nanhua Hamatake, Robert Hong, Zhi Wu, Jim Z. |
| description | A novel class of pyridone-based inhibitors of Pim-1 kinase is reported. A complex crystal structure of Pim-1/compound
1 (IC
50 of
1
=
50
nM) defined an inhibitory mechanism of action.
A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC
50
=
50
nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R
1 phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor. |
| doi_str_mv | 10.1016/j.bmcl.2006.12.086 |
| format | article |
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1 (IC
50 of
1
=
50
nM) defined an inhibitory mechanism of action.
A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC
50
=
50
nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R
1 phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2006.12.086</identifier><identifier>PMID: 17251021</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Adenosine Triphosphate - metabolism ; Biological and medical sciences ; Cloning, Molecular ; Crystallography, X-Ray ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - pharmacology ; Fused-ring pyridone ; Humans ; Hydrogen Bonding ; Indicators and Reagents ; Medical sciences ; Miscellaneous ; Models, Molecular ; Molecular Conformation ; Molecular Sequence Data ; Pharmacology. Drug treatments ; Pim ; Pim-1 ; Pim-1 kinase ; Pim-1 kinase inhibitors ; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors ; Proto-Oncogene Proteins c-pim-1 - chemical synthesis ; Proto-Oncogene Proteins c-pim-1 - genetics ; Pyridone ; Pyridones - chemical synthesis ; Pyridones - pharmacology ; Recombinant Proteins - chemistry ; Reverse Transcriptase Polymerase Chain Reaction ; Structure-Activity Relationship ; X-ray complex structure</subject><ispartof>Bioorganic & medicinal chemistry letters, 2007-03, Vol.17 (6), p.1679-1683</ispartof><rights>2007 Elsevier Ltd</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-643271e1005a507e192b76e13373bc774208dcf28faa352ffe977d94afad17ef3</citedby><cites>FETCH-LOGICAL-c481t-643271e1005a507e192b76e13373bc774208dcf28faa352ffe977d94afad17ef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18618847$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17251021$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheney, I. Wayne</creatorcontrib><creatorcontrib>Yan, Shunqi</creatorcontrib><creatorcontrib>Appleby, Todd</creatorcontrib><creatorcontrib>Walker, Heli</creatorcontrib><creatorcontrib>Vo, Todd</creatorcontrib><creatorcontrib>Yao, Nanhua</creatorcontrib><creatorcontrib>Hamatake, Robert</creatorcontrib><creatorcontrib>Hong, Zhi</creatorcontrib><creatorcontrib>Wu, Jim Z.</creatorcontrib><title>Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A novel class of pyridone-based inhibitors of Pim-1 kinase is reported. A complex crystal structure of Pim-1/compound
1 (IC
50 of
1
=
50
nM) defined an inhibitory mechanism of action.
A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC
50
=
50
nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R
1 phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cloning, Molecular</subject><subject>Crystallography, X-Ray</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fused-ring pyridone</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>Indicators and Reagents</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Sequence Data</subject><subject>Pharmacology. Drug treatments</subject><subject>Pim</subject><subject>Pim-1</subject><subject>Pim-1 kinase</subject><subject>Pim-1 kinase inhibitors</subject><subject>Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-pim-1 - chemical synthesis</subject><subject>Proto-Oncogene Proteins c-pim-1 - genetics</subject><subject>Pyridone</subject><subject>Pyridones - chemical synthesis</subject><subject>Pyridones - pharmacology</subject><subject>Recombinant Proteins - chemistry</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Structure-Activity Relationship</subject><subject>X-ray complex structure</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNqF0c9u1DAQBnALgehSeAEOKBe4JXgcJ44lLqgqpVIlOIDEzXLssTpL_iy2U2lvvANvyJM0212pNzjN5TefRvMx9hp4BRza99uqH91QCc7bCkTFu_YJ24BsZVlL3jxlG65bXnZa_jhjL1Lacg6SS_mcnYESDXABGzZce5wyBXI20zwVdvJFynFxeYn49_cf6zLdUd4XEYcHkW5pl4o5FGnpU6a8ZPTFbh_JzxOmwqaCplvqKc_xgX2lsYTiJ0024Uv2LNgh4avTPGffP11-u_hc3ny5ur74eFM62UEuW1kLBQicN7bhCkGLXrUIda3q3iklBe-8C6IL1taNCAG1Ul5LG6wHhaE-Z--Oubs4_1owZTNScjgMdsJ5SabVvNYgxX8h6AZ0rbsViiN0cU4pYjC7SKONewPcHMowW3MowxzKMCDMWsa69OaUvvQj-seV0_dX8PYEbHJ2CNFOjtKj61roOqlW9-HocH3aHWE0yRFODj1FdNn4mf51xz032aqx</recordid><startdate>20070315</startdate><enddate>20070315</enddate><creator>Cheney, I. Wayne</creator><creator>Yan, Shunqi</creator><creator>Appleby, Todd</creator><creator>Walker, Heli</creator><creator>Vo, Todd</creator><creator>Yao, Nanhua</creator><creator>Hamatake, Robert</creator><creator>Hong, Zhi</creator><creator>Wu, Jim Z.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20070315</creationdate><title>Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase</title><author>Cheney, I. Wayne ; Yan, Shunqi ; Appleby, Todd ; Walker, Heli ; Vo, Todd ; Yao, Nanhua ; Hamatake, Robert ; Hong, Zhi ; Wu, Jim Z.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-643271e1005a507e192b76e13373bc774208dcf28faa352ffe977d94afad17ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Biological and medical sciences</topic><topic>Cloning, Molecular</topic><topic>Crystallography, X-Ray</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Fused-ring pyridone</topic><topic>Humans</topic><topic>Hydrogen Bonding</topic><topic>Indicators and Reagents</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Sequence Data</topic><topic>Pharmacology. Drug treatments</topic><topic>Pim</topic><topic>Pim-1</topic><topic>Pim-1 kinase</topic><topic>Pim-1 kinase inhibitors</topic><topic>Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-pim-1 - chemical synthesis</topic><topic>Proto-Oncogene Proteins c-pim-1 - genetics</topic><topic>Pyridone</topic><topic>Pyridones - chemical synthesis</topic><topic>Pyridones - pharmacology</topic><topic>Recombinant Proteins - chemistry</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Structure-Activity Relationship</topic><topic>X-ray complex structure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheney, I. Wayne</creatorcontrib><creatorcontrib>Yan, Shunqi</creatorcontrib><creatorcontrib>Appleby, Todd</creatorcontrib><creatorcontrib>Walker, Heli</creatorcontrib><creatorcontrib>Vo, Todd</creatorcontrib><creatorcontrib>Yao, Nanhua</creatorcontrib><creatorcontrib>Hamatake, Robert</creatorcontrib><creatorcontrib>Hong, Zhi</creatorcontrib><creatorcontrib>Wu, Jim Z.</creatorcontrib><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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheney, I. Wayne</au><au>Yan, Shunqi</au><au>Appleby, Todd</au><au>Walker, Heli</au><au>Vo, Todd</au><au>Yao, Nanhua</au><au>Hamatake, Robert</au><au>Hong, Zhi</au><au>Wu, Jim Z.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2007-03-15</date><risdate>2007</risdate><volume>17</volume><issue>6</issue><spage>1679</spage><epage>1683</epage><pages>1679-1683</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A novel class of pyridone-based inhibitors of Pim-1 kinase is reported. A complex crystal structure of Pim-1/compound
1 (IC
50 of
1
=
50
nM) defined an inhibitory mechanism of action.
A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC
50
=
50
nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R
1 phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>17251021</pmid><doi>10.1016/j.bmcl.2006.12.086</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2007-03, Vol.17 (6), p.1679-1683 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_69039142 |
| source | ScienceDirect Journals |
| subjects | Adenosine Triphosphate - metabolism Biological and medical sciences Cloning, Molecular Crystallography, X-Ray Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Fused-ring pyridone Humans Hydrogen Bonding Indicators and Reagents Medical sciences Miscellaneous Models, Molecular Molecular Conformation Molecular Sequence Data Pharmacology. Drug treatments Pim Pim-1 Pim-1 kinase Pim-1 kinase inhibitors Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors Proto-Oncogene Proteins c-pim-1 - chemical synthesis Proto-Oncogene Proteins c-pim-1 - genetics Pyridone Pyridones - chemical synthesis Pyridones - pharmacology Recombinant Proteins - chemistry Reverse Transcriptase Polymerase Chain Reaction Structure-Activity Relationship X-ray complex structure |
| title | Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase |
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