Pyrido[2,3-d]pyrimidin-7-one Inhibitors of Cyclin-Dependent Kinases
The identification of 8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear...
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| Veröffentlicht in: | Journal of medicinal chemistry 2000-11, Vol.43 (24), p.4606-4616 |
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| container_title | Journal of medicinal chemistry |
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| creator | Barvian, Mark Boschelli, Diane H Cossrow, Jennifer Dobrusin, Ellen Fattaey, Ali Fritsch, Alex Fry, David Harvey, Patricia Keller, Paul Garrett, Michelle La, Frances Leopold, Wilbur McNamara, Dennis Quin, Maire Trumpp-Kallmeyer, Susanne Toogood, Peter Wu, Zhipei Zhang, Erli |
| description | The identification of 8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC50 = 0.004 μM ([ATP] = 25 μM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb+ cells in the G1-phase of the cell division cycle. |
| doi_str_mv | 10.1021/jm000271k |
| format | Article |
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Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC50 = 0.004 μM ([ATP] = 25 μM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb+ cells in the G1-phase of the cell division cycle.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm000271k</identifier><identifier>PMID: 11101352</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; Antineoplastic agents ; Biological and medical sciences ; CDC2-CDC28 Kinases ; Cell Division - drug effects ; Cell Line ; Crystallography, X-Ray ; Cyclin-Dependent Kinase 2 ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinases - antagonists & inhibitors ; Cyclin-Dependent Kinases - metabolism ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; General aspects ; Humans ; Insecta - cytology ; Kinetics ; Medical sciences ; Models, Molecular ; Pharmacology. Drug treatments ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Recombinant Proteins - antagonists & inhibitors ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2000-11, Vol.43 (24), p.4606-4616</ispartof><rights>Copyright © 2000 American Chemical Society</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a377t-21fd456852fca64583136a2d9dbe697aadf634b53a54f38addb633563f07c0f53</citedby><cites>FETCH-LOGICAL-a377t-21fd456852fca64583136a2d9dbe697aadf634b53a54f38addb633563f07c0f53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm000271k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm000271k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=832513$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11101352$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barvian, Mark</creatorcontrib><creatorcontrib>Boschelli, Diane H</creatorcontrib><creatorcontrib>Cossrow, Jennifer</creatorcontrib><creatorcontrib>Dobrusin, Ellen</creatorcontrib><creatorcontrib>Fattaey, Ali</creatorcontrib><creatorcontrib>Fritsch, Alex</creatorcontrib><creatorcontrib>Fry, David</creatorcontrib><creatorcontrib>Harvey, Patricia</creatorcontrib><creatorcontrib>Keller, Paul</creatorcontrib><creatorcontrib>Garrett, Michelle</creatorcontrib><creatorcontrib>La, Frances</creatorcontrib><creatorcontrib>Leopold, Wilbur</creatorcontrib><creatorcontrib>McNamara, Dennis</creatorcontrib><creatorcontrib>Quin, Maire</creatorcontrib><creatorcontrib>Trumpp-Kallmeyer, Susanne</creatorcontrib><creatorcontrib>Toogood, Peter</creatorcontrib><creatorcontrib>Wu, Zhipei</creatorcontrib><creatorcontrib>Zhang, Erli</creatorcontrib><title>Pyrido[2,3-d]pyrimidin-7-one Inhibitors of Cyclin-Dependent Kinases</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The identification of 8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC50 = 0.004 μM ([ATP] = 25 μM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb+ cells in the G1-phase of the cell division cycle.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>CDC2-CDC28 Kinases</subject><subject>Cell Division - drug effects</subject><subject>Cell Line</subject><subject>Crystallography, X-Ray</subject><subject>Cyclin-Dependent Kinase 2</subject><subject>Cyclin-Dependent Kinase 4</subject><subject>Cyclin-Dependent Kinases - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>General aspects</subject><subject>Humans</subject><subject>Insecta - cytology</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0FtLIzEUB_AgK1ovD_sFlsKiIBhNcibJ-Cj1bsXLdllQlpCZJGzqNFOTKdhvb6Sl--JTODk_Duf8EfpOyREljB6PJ4QQJunrGupRzgguSlJ8Q738yTATDDbRVkrjjIAy2ECblFJCgbMeGjzMozftCzsEbP5OczHxxgcscRts_zr885Xv2pj6resP5nWTW2d2aoOxoevf-qCTTTto3ekm2d3lu41-X5yPBld4eH95PTgdYg1SdphRZwouSs5crUXBS6AgNDMnprLiRGptnICi4qB54aDUxlQCgAtwRNbEcdhG-4u509i-zWzq1MSn2jaNDradJSWZILKkNMODBaxjm1K0Tk3zXTrOFSXqMzG1SizbH8uhs2pizX-5jCiDn0ugU60bF3WofVq5EhinkBVeKJ86-77q6viqhATJ1ejhl_rz_Di6eZJDdZf93sLrOqlxO4shJ_fFeh95JIw-</recordid><startdate>20001130</startdate><enddate>20001130</enddate><creator>Barvian, Mark</creator><creator>Boschelli, Diane H</creator><creator>Cossrow, Jennifer</creator><creator>Dobrusin, Ellen</creator><creator>Fattaey, Ali</creator><creator>Fritsch, Alex</creator><creator>Fry, David</creator><creator>Harvey, Patricia</creator><creator>Keller, Paul</creator><creator>Garrett, Michelle</creator><creator>La, Frances</creator><creator>Leopold, Wilbur</creator><creator>McNamara, Dennis</creator><creator>Quin, Maire</creator><creator>Trumpp-Kallmeyer, Susanne</creator><creator>Toogood, Peter</creator><creator>Wu, Zhipei</creator><creator>Zhang, Erli</creator><general>American Chemical Society</general><scope>BSCLL</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>7X8</scope></search><sort><creationdate>20001130</creationdate><title>Pyrido[2,3-d]pyrimidin-7-one Inhibitors of Cyclin-Dependent Kinases</title><author>Barvian, Mark ; Boschelli, Diane H ; Cossrow, Jennifer ; Dobrusin, Ellen ; Fattaey, Ali ; Fritsch, Alex ; Fry, David ; Harvey, Patricia ; Keller, Paul ; Garrett, Michelle ; La, Frances ; Leopold, Wilbur ; McNamara, Dennis ; Quin, Maire ; Trumpp-Kallmeyer, Susanne ; Toogood, Peter ; Wu, Zhipei ; Zhang, Erli</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a377t-21fd456852fca64583136a2d9dbe697aadf634b53a54f38addb633563f07c0f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>CDC2-CDC28 Kinases</topic><topic>Cell Division - drug effects</topic><topic>Cell Line</topic><topic>Crystallography, X-Ray</topic><topic>Cyclin-Dependent Kinase 2</topic><topic>Cyclin-Dependent Kinase 4</topic><topic>Cyclin-Dependent Kinases - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinases - metabolism</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>General aspects</topic><topic>Humans</topic><topic>Insecta - cytology</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barvian, Mark</creatorcontrib><creatorcontrib>Boschelli, Diane H</creatorcontrib><creatorcontrib>Cossrow, Jennifer</creatorcontrib><creatorcontrib>Dobrusin, Ellen</creatorcontrib><creatorcontrib>Fattaey, Ali</creatorcontrib><creatorcontrib>Fritsch, Alex</creatorcontrib><creatorcontrib>Fry, David</creatorcontrib><creatorcontrib>Harvey, Patricia</creatorcontrib><creatorcontrib>Keller, Paul</creatorcontrib><creatorcontrib>Garrett, Michelle</creatorcontrib><creatorcontrib>La, Frances</creatorcontrib><creatorcontrib>Leopold, Wilbur</creatorcontrib><creatorcontrib>McNamara, Dennis</creatorcontrib><creatorcontrib>Quin, Maire</creatorcontrib><creatorcontrib>Trumpp-Kallmeyer, Susanne</creatorcontrib><creatorcontrib>Toogood, Peter</creatorcontrib><creatorcontrib>Wu, Zhipei</creatorcontrib><creatorcontrib>Zhang, Erli</creatorcontrib><collection>Istex</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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barvian, Mark</au><au>Boschelli, Diane H</au><au>Cossrow, Jennifer</au><au>Dobrusin, Ellen</au><au>Fattaey, Ali</au><au>Fritsch, Alex</au><au>Fry, David</au><au>Harvey, Patricia</au><au>Keller, Paul</au><au>Garrett, Michelle</au><au>La, Frances</au><au>Leopold, Wilbur</au><au>McNamara, Dennis</au><au>Quin, Maire</au><au>Trumpp-Kallmeyer, Susanne</au><au>Toogood, Peter</au><au>Wu, Zhipei</au><au>Zhang, Erli</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pyrido[2,3-d]pyrimidin-7-one Inhibitors of Cyclin-Dependent Kinases</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2000-11-30</date><risdate>2000</risdate><volume>43</volume><issue>24</issue><spage>4606</spage><epage>4616</epage><pages>4606-4616</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The identification of 8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC50 = 0.004 μM ([ATP] = 25 μM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb+ cells in the G1-phase of the cell division cycle.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11101352</pmid><doi>10.1021/jm000271k</doi><tpages>11</tpages></addata></record> |
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| subjects | Adenosine Triphosphate - metabolism Animals Antineoplastic agents Biological and medical sciences CDC2-CDC28 Kinases Cell Division - drug effects Cell Line Crystallography, X-Ray Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases - antagonists & inhibitors Cyclin-Dependent Kinases - metabolism Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General aspects Humans Insecta - cytology Kinetics Medical sciences Models, Molecular Pharmacology. Drug treatments Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Recombinant Proteins - antagonists & inhibitors Structure-Activity Relationship |
| title | Pyrido[2,3-d]pyrimidin-7-one Inhibitors of Cyclin-Dependent Kinases |
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